In elderly patients with a SCr less than 1 mg/dL, a value of “1” should be used for the SCr in this equation to avoid overestimating CrCl. Although the Cockcroft-Gault formula is frequently used to both assess renal function and to make dosage adjustments of renally excreted drugs, it is important for clinicians to be aware that this equation tends to underestimate the glomerular filtration rate (GFR) of older adults.[21] Most recently, the Modification of Diet in Renal Disease (MDRD) equation is being advocated as an alternative method for assessing renal function because it appears to have a better correlation with GFR when compared with the Cockcroft-Gault formula.[22, 23] Moreover, although the MDRD equation was derived from patients with chronic kidney disease, it has been shown to provide a more accurate estimate of renal function in the elderly when compared to the Cockcroft-Gault formula.[24] However, because the MDRD equation has not been validated for use in adjusting drug dosages, health-care providers should continue to use the Cockcroft-Gault formula for this purpose.
Pharmacodynamic changes
A number of age-related physiologic changes may occur that increase or decrease sensitivity to a drug. Mechanisms for altered age-related pharmacodynamics include changes in receptor number and affinity, changes in drug concentrations at the receptor, alterations in postreceptor signaling, and alterations in homeostatic mechanisms.[25] In the cardiovascular system, because of the decline in β-receptor activity that occurs with age, a decline in β-adrenergic responsiveness may occur which could minimize heart rate response to both β-agonists and β-blockers.[26] Older adults also have a lessened reduction in blood pressure from β-blockers.[25] Additionally, blunting of the baroreceptor reflex can occur with aging, resulting in the development of exaggerated postural hypotensive effects during therapy with drugs such as nitrates, diuretics, calcium channel blockers, and α1 blockers.[27, 28] Changes in the pharmacodynamics of central nervous system agents may also occur, including alterations in the permeability of the blood brain barrier and changes in brain size and alterations of neurotransmitters.[25] The overall result of these changes is an increased sensitivity to central nervous system agents. Although no significant differences in the pharmacokinetics of warfarin have been demonstrated between younger and older patients, the pharmacodynamics of this drug may be altered in the elderly population, potentially resulting in an enhanced anticoagulant effect and an increased risk of bleeding.[25, 28] Consequently, it may be prudent for health-care providers to use lower initial and maintenance doses of warfarin in this population.
Beers Criteria
Older adults are particularly susceptible to inappropriate prescribing due to age-related pharmacokinetic and pharmacodynamic changes, increased comorbidities, increased risk of drug interactions, polypharmacy, and adverse drug reactions. The use of medication is considered potentially inappropriate when the possible risk outweighs the expected clinical benefit. The Beers Criteria, initially developed by an expert panel in 1991 to target nursing home residents, are the most widely cited criteria used to identify high risk, or “potentially inappropriate,” medication in older adults.[29] The Beers Criteria are now in a fourth permutation, having been most recently updated in 2012, and are intended for use by clinicians in both inpatient and community settings. The current criteria include three groups of medications: medications to avoid in older adults regardless of disease or condition (e.g., barbiturates, megestrol, glyburide, and sliding scale insulin); medications to avoid when used in older adults with certain diseases or conditions (e.g., avoidance of medications with anticholinergic properties in patients with cognitive impairment); and a new, third group of medications that should be prescribed with universal caution (dabigatran, SSRIs).[30] Numerous studies have evaluated health-care outcomes associated with the use of the potentially inappropriate drugs included in the Beers Criteria. There is clear evidence that inappropriate medication use is associated with adverse drug reactions and increased costs across all health-care settings (ambulatory, acute, and long-term care).[31]
Although the Beers Criteria have been increasingly used as a quality-of-care measure (as evidenced by the Beers-like list of inappropriate drugs adopted by the 2006 Health Plan Employer and Data and Information Set [HEDIS]), the criteria have been criticized for using an explicit method that may not take clinical application into account for assessing drug therapy appropriateness.[32, 33] In an effort to highlight the possibility of criteria misuse or misinterpretation, the American Medical Directors Association and the American Society of Consultant Pharmacists have released a position statement identifying the Beers Criteria as a “helpful general guide.”[34] Clinicians are warned against inappropriately using the criteria as an absolute prohibition against specific medications in older adults. Instead, clinicians are encouraged to make prescribing decisions in the context of a complete clinical picture that includes the entire medication regimen, history of medication use, comorbidities, functional status, and prognosis.
STOPP/START criteria
The STOPP (Screening Tool of Older People’s potentially inappropriate Prescriptions) and START (Screening Tool to Alert doctors to the Right Treatment) criteria were developed to address limitations observed in the Beers Criteria. STOPP is comprised of clinically significant criteria for potentially inappropriate prescribing. Each criterion is supported by a concise explanation as to why the prescribing practice is potentially inappropriate and includes consideration of drug–drug interactions and duplication of therapy. START consists of evidence-based prescribing indicators for commonly encountered diseases.[35] In two studies, the STOPP critiera identified a significantly higher percentage of older patients requiring hospitalization as a result of an adverse drug event (ADE) than did the 2003 Beers Criteria.[36, 37]
Adverse drug reactions in the elderly: an overview
Adverse drug reactions (ADRs) are noxious responses to medications used in usual doses that require treatment of the effect, modification of the drug regimen, or cessation of treatment.38 The incidence of hospital admissions caused by ADRs in older adults, many of which are avoidable, ranges from 3% to 10%.[33, 39] The prevalence of ADRs in older outpatients ranges from 5% to 35%.[40] The consequences associated with ADRs are not insignificant; studies have demonstrated that the cost of ADRs adds a financial burden to an already overspent health-care system.[41, 42]
ADRs in older adults are frequently exaggerated responses to expected pharmokinetic and pharmacodynamic shifts. Polypharmacy, a common occurrence in this population, increases the risk of ADRs due to drug interactions, synergistic toxic effects, and nonadherence to complicated or expensive medication regimens. Decreased mobility, multiple disease states, low body weight, renal and/or hepatic dysfunction, female sex, and a prior history of ADRs further increase the risk for the development of ADRs.[40]
Common ADRs in the elderly include an increased risk of falls, changes in mental status, and effects on urinary continence. Table 5.2 identifies some of the common pharmacologic agents that may cause each of these ADRs.
Adverse drug reactions: falls
Falls are of significant concern because of their associated morbidity and mortality. Nearly one-third of adults over the age of 65 fall at least once per year.[43] Approximately 10% of such falls result in serious injury, most notably hip fractures, with up to 75% of hip fracture patients failing to regain their prior level of function.[44, 45] Fall-related injuries are associated with a decline in functional status and an increased likelihood of nursing home placement.[46] In one study, 20% of elderly patients who experienced a hip fracture died within a year of the fracture.[46]
Medication use is one of the most modifiable risk factors for falls.[45] Polypharmacy may be a marker of underlying comorbidity and frailty, rendering a patient more susceptible to falling. Regardless of whether agents are considered to be high risk, falls are more common in elderly patients who take more than four drugs per day.[47] Risk of medication-related falls can be mitigated through patient education, slow dose titration, and avoidance of polypharmacy and high-risk medication when possible. Certain medication classes, when used alone or in combination with other medications, can increase fall risk.[47] Psychotropic and antidepressant medications are frequently prescribed in the elderly to treat depression, psychosis, and insomnia and may increase fall risk when taken with other medications that carry a high-risk profile. Antipsychotic medications can cause many adverse effects, including extrapyramidal symptoms, orthostasis, and cognitive impairment.[48] These effects are more commonly associated with the typical antipsychotics (e.g., haloperidol, thiothixine, droperidol), but they have also been documented with the newer atypical agents (quetiapine, risperidone, olanzapine).[48, 49] The anticholinergic properties of sedation, orthostatic hypotension, and confusion associated with tricyclic antidepressants (TCAs) were one of the original perceived barriers to prescribing in older adults. Although selective serotonin reuptake inhibitors (SSRIs) cause markedly less sedation, studies suggest that SSRIs are associated with fall rates similar to the TCAs.[50, 51]
Benzodiazepines have been implicated in increasing fall risk. It is frequently stated that short-acting benzodiazepines are safer than long-acting benzodiazepines for the elderly. However, this distinction may be blurred, as the pharmacokinetic half-life of benzodiazepines in the blood may be misleadingly short compared with the duration of pharmacodynamic effects on the nervous system.[52] It is likely that risk increases with increasing dose; therefore, if benzodiazepines must be used, the lowest dose should be used for the shortest duration possible.[48, 50]
The use of opioid analgesics, with proper monitoring, is increasingly recognized as a reasonable option for treating pain in older patients, despite persistent misconceptions about addictive potential and the real concern for sedation and fall risk.[53] The risk of addiction in patients using opioids appropriately for pain is low.[53] Although there is contradicting data on whether opioids cause falls, adequate pain control may be warranted for patients with regard to quality of life. Careful selection of agent and dose, titration, and use of adjunct agents should be considered to minimize risk.[54, 55]
Any agent that causes hypotension or dizziness may increase fall risk. Agents such as α1 blockers, which are used to treat benign prostatic hypertrophy, commonly cause dizziness.[56] Evidence linking fall risk with antihypertensive agents, however, is mixed. Some studies show that patients have an increased risk with these agents whereas others do not.[54] It has been demonstrated in observational studies that type Ia antiarrhythmics, digoxin, and diuretics are associated with increased fall rates.[54] Because these agents are commonly used in the older adult population, it is important to educate patients about the risk of falls due to hypotension or dizziness and preventative measures that can be taken. Whenever possible, antihypertensives and other agents known to cause dizziness should be dosed at bedtime in order to decrease risk.[57]
Adverse drug reactions: cognitive impairment
Patients with an acute illness, such as a urinary tract infection, or a worsening chronic condition, such as heart failure, can present with cognitive dysfunction in the form of confusion or mental status changes.[58, 59] Many commonly used medications can also precipitate or contribute to the development of cognitive disturbances. It can be challenging for the practitioner to distinguish between cognitive impairment secondary to a disease process versus a medication. It is, therefore, appropriate to consider the possibility that changes in cognitive function may be partially or wholly due to medications.[60]
Any medication with central nervous system (CNS) effects has the potential to cause cognitive dysfunction. Opioid analgesics can cause sedation, confusion, and even hallucinations.[61] Amphetamines cause CNS stimulation and excitation, effects that are often exaggerated in the elderly.[61] Antipsychotics, used to treat behavioral problems as well as psychotic disorders, can cause anticholinergic-associated cognitive impairment.[49] A small observational trial demonstrated significant cognitive decline in patients with dementia who used neuroleptic agents compared with those who did not.[62] Anticholinergic agents are frequently responsible for causing CNS disturbances such as confusion, excitement, disorientation, and delirium.[56] Many commonly used medications, including over-the-counter antihistamines (diphenhydramine, chlorpheniramine), as well as prescription-only antidepressants (e.g., amitriptyline, doxepin, imipramine), skeletal muscle relaxants (cyclobenzaprine, orphenadrine), and bronchodilators (atropine and ipratropium) have anticholinergic actions.[49, 63, 64] Risk of cognitive impairment increases with the number of medications used, especially anticholinergic agents.[49, 61] Anticholinergic-associated cognitive dysfunction may also potentiate preexisting cognitive impairment.[49, 63] Physicians must be aware of an agent’s potential to cause cognitive dysfunction and must consider the “anticholinergic burden” of a patient’s entire medication regimen when prescribing. Whereas a single medication may not result in anticholinergic-associated cognitive changes, the use of multiple drugs with such effects may increase that risk.[63]
Drug prescribing patterns: underutilization of drug therapy
Whereas extensive research has focused on overprescribing for older adults; underprescribing appropriate medications is increasingly recognized as a potential clinical pitfall. In fact, clinicians may avoid overprescribing inappropriate drug therapies while underprescribing indicated therapies.[65] The interconnectedness of polypharmacy and undertreatment has been repeatedly illustrated, and studies have demonstrated that the probability of underprescribing increases as the size of a patient’s drug regimen increases.[66, 67] Undertreatment of medical conditions has been observed to occur in 64%–83% of elderly patients receiving more than five medications.[66, 67]
The highest incidence of undertreatment has been observed with laxatives used to prevent constipation in patients receiving chronic opioids, and with ACE inhibitor and β-blocker use in cardiovascular disease.[66, 68] Other agents underused in the geriatric population include antihypertensives, aspirin, antihyperlipidemics, oral hypoglycemic agents, and calcium supplements.[67, 68] In a study of patients with coronary artery disease in an academic nursing home, only 62% received aspirin, 58% received an ACE-inhibitor or an angiotensin II receptor blocker, 57% received a β-blocker, 27% received a calcium channel blocker, and 21% received a statin.[68] None of these patients had a contraindication to the agents with which they were not treated.
In evaluating ways to minimize both polypharmacy and the underutilization of well-studied and supported therapeutic initiatives, a collaborative approach has been observed.[69] When the addition of a clinical pharmacist to the geriatric team (Geriatric Evaluation and Management [GEM] care) was compared to the use of the GEM alone, intervention patients (stratified by age and number of medications) were more likely to benefit from a clinically appropriate medication regimen.[69]
Drug adherence
The true rate of medication adherence is estimated to be 50%, with a range of 26%–59% in patients aged 60 and older.[70] As many as 10% of hospital admissions and 23% of nursing home admissions may be attributed to medication nonadherence.[70] Seventy-five percent of hospital admissions related to nonadherence involved cardiovascular and CNS medications. Falls, postural hypotension, heart failure, and delirium were the most common manifestations of nonadherence.[70]
Factors affecting drug adherence
Once an optimal therapeutic regimen is determined for a patient, adherence becomes a key component to therapeutic success. “Adherence” is a preferred term to “compliance” as it implies a collaborative relationship between the patient and/or caregiver and the health-care provider. “Compliance,” in comparison, implies a one-way relationship wherein the health-care provider makes all decisions and provides “directions” independent of the wants and needs of the patient.[71]
Factors that affect medication adherence include demographics (e.g., occupation, level of education, and health literacy), medical parameters (type, severity, and duration of disease), medication profile (complexity of regimen and side-effect profile), behavioral factors (patient-provider communication and patient health beliefs), and economic constraints (type of insurance, cost of medication, and patient income). The elderly are at high risk of nonadherence.[72]
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