GERIATRIC PHARMACOLOGY

1. How do the changes associated with aging seen with lean body mass and body fat affect the volume of distribution of hydrophilic and lipophilic medications? 2. What would be the pharmacokinetic characteristics of the ideal drug for use with older patients? 3. What changes occur in Phase I metabolism as compared to Phase II metabolism in elderly patients? 4. Why are the changes in pharmacodynamics important to consider when choosing and dosing a medication for an elderly patient? In the elderly, there is an increased ? to the effects of many drugs. As an example, geriatric patients exhibit a greater sensitivity to the effects of drugs that gain access to the CNS (e.g., benzodiazepines (BZ; anxiolytic, sedative/hypnotic), cimetidine (histamine H2 antagonist)). In most cases, lower doses are required for adequate response, and patients have a higher incidence of adverse effects. For example, lower doses of opioids provide sufficient pain relief for older patients, whereas conventional doses can cause over-sedation and respiratory depression. Similarly, elderly patients appear of be more sensitive to the ? effects of BZ. Sedation is induced by diazepam at lower doses and lower plasma concentrations in elderly patients. The sensitivity of the elderly to BZ and their effects last longer than in the young. It is common clinical experience that BZ given to the elderly at hypnotic doses used for the young can produce ? even after single doses. Similarly, the incidence of confusion associated with ? is increased in the elderly. Among the more serious complications, ? that lead to hip fracture have been associated with increasing dosages and prolonged half-lives of psychotropic drugs, including antidepressants and BZ. Therefore, these drugs should be initiated at lower doses than those used for younger patients and titrated slowly for safe and appropriate sedation. Also, agents with a favorable pharmacokinetic profile (e.g., rapid onset and relatively brief duration) should be chosen. For example, start with very low doses of BZ and titrate slowly, longer interval between doses, and closely monitoring the patient for any adverse response. Furthermore, choose lorazepam or oxazepam due to their hydrophilic properties and Phase II metabolism. 5. What proportion of adverse drug reactions (ADRs) are considered preventable? ? of ADRs are considered preventable. 6. Why are elderly patients more or less vulnerable to hospitalization due to ADRs relative to younger patients? 7. What risk factor for ADRs is most consistently described in the literature? ? 8. In which category (prescribing, monitoring, dispensing, or administration) do the majority of adverse drug events occur?

-Decreased lean body mass and total body water--> Reduction of the half-lives of hydrophilic drugs since their volume of distribution is reduced. -Increased body fat--> Lipophilic medications exhibit an increase in volume of distribution and half-life. -Rapid onset and relatively brief duration. If possible use drugs that undergo Phase II metabolism. See below for further explanation. -Decreased elimination rate of drugs that undergo oxidative Phase I metabolism. Age does not have an effect on Phase II hepatic metabolism. -sensitivity -sedating -prolonged daytime confusion -cimetidine -falls -50% -The elderly often take many more drugs than their younger counterparts. Consequently, this polypharmacy adds to risk. -poly-pharmacy -Inappropriate prescribing.

PHARMACOKINETIC CHANGES Absorption: Multiple changes occur throughout the GI tract with aging (Figure 1; Table 1), but little evidence indicates that drug absorption is significantly altered. Distribution: Elderly patients can undergo significant structural changes in the body that alter drug distribution, half-life, and duration of action. Main factors that affect distribution of drugs in the body are changes in ? and ? (Figure 2; Table 2) and changes in ? (Table 3). Metabolism: Drug metabolism is affected by age, acute and chronic diseases, and drug-drug interactions. The ? is the primary site of drug metabolism, which undergoes changes with age (Figure 3; Table 4). Excretion: The most clinically important pharmacokinetic change in the elderly is the decrease in ? (Figure 4; Table 5). Longitudinal studies indicate that the GFR drops on average by 1% for every year of age past 20 so that the oldest old who have survived six decades since their twentieth birthday will very likely have GFRs of less than ? mL/min (Figure 5). Direct measurement of the GFR requires a 24-hour urine collection which is inconvenient and time-consuming for the patient, so most clinicians use an equation to estimate GFR or creatinine clearance (CrCl), to evaluate a patient's renal function. CrCl, an estimate of GFR, should always be calculated when starting or adjusting drugs in the elderly. The Cockcroft-Gault equation is the most widely used formula for estimating renal function and adjusting drug doses and best validated for use in patients over 75 years of age (Figure 6). The Cockcroft-Gault equation corrects for age-associated changes in creatinine production based on population parameters. It incorporates 4 things?. The resulting CrCl is in units of mL/min. For women, multiply this result by 0.85. What is the equation?

-body fat and water, protein binding -liver -renal drug elimination -59 -serum creatinine concentration (SCr, mg/dL), age (years), gender, and weight (Wt.; kilograms) CrCl= ((140-age)*Wt / SCr * 72) * (0.85) if a women

II. INTRODUCTION The growth of the aging population and increasing lifespan require that we have the knowledge necessary to meet the needs of this patient group. The pharmaceutical care of older adults differs from that of younger adults for multiple reasons. People aged over 65 years are at higher risk for diseases (cancer, cardiovascular diseases, neurological disorders) and specific diseases/problems of elderly people such as ? and ? . As a result, this group is the greatest consumer of prescription drugs. Elderly people often use various drugs at the same time, resulting in the risk of unwanted drug interactions and adverse drug events. These aspects combined with the fact, that elderly people develop decreased functions of heart, lungs, kidneys, liver etc. count for the danger of other disease symptoms, like confusion, constipation and falls. These notes address the pharmacokinetics, pharmacodynamics and drug interactions in the elderly. When these factors are considered prior treatment, drug-related problems can be minimized. My goal is to help you to understand what it means to prescribe, dispense and administer medications, but most importantly, manage a combination of those medications safely without causing harm. III. EPIDEMIOLOGY OF AGING A chronological definition is often used to stratify the aging population into three groups: young old, age ?; old, age ? years; and old old, age ≥ ? years. Population aging is an incontrovertible trend. In 2010, 40.3 million U.S. residents were 65 years and older (13% of the total population), nearly 5.5 million people were 85 years and older (the "oldest-old"), and over 53,000 were centenarians. People over 65 years are projected to increase up to 72 million in 2030, representing 20% of the total U.S. population. In fact, the oldest (85 years and older) are projected to be the fastest growing part of the elderly population in the coming years (projected to increase up to 19 million in 2050 and make up 5% of the total US population). There are more ? than ? in the older population. In 2010, there were a total of 22.9 million women and 17.4 million men (an average ratio of 100 women to 77.3 men) 65 years and older; the ratio widens as elders age. IV. AGE-RELATED PHYSIOLOGICAL CHANGES In basic terms, pharmacokinetics is what the body does to the drug, and pharmacodynamics is what the drug does to the body. All four components of pharmacokinetics - absorption, distribution (volume of distribution (Vd) and transport), metabolism, and excretion - are affected by aging. The most clinically important and consistent is the reduction of ? of drugs.

-incontinence, dementia -65-75, 75-85, 85-95 -women, men -renal elimination

GERIATRIC ASSESSMENT PRINCIPLES OF GERIATRIC PRESCRIBING/PATIENT CARE AND MONITORING: The general principles of rationally prescribing for geriatric patients do not differ in any essential way from those that apply to patients of any age. Nevertheless, because of multiple diseases, the need for multiple medications, the potential for altered drug response, and the increased occurrence of unwanted drug effects, the physician must be cautious and monitor therapy carefully. Because of these factors, variability of drug response is much greater in elderly populations. In addition, impaired homeostatic mechanisms in these patients may increase the risk and severity of drug-induced toxicity. Drug-related problems in the elderly patient can be identified by performing a comprehensive medication review. Principles of Geriatric Prescribing Complete ? Have the patient bring all of their medication bottles - Prescription medications - OTC drugs - Vitamin supplements - Herbal products Take a careful history of habits and drug use - Smoking, alcohol, and caffeine Know the ? Use a few drugs well Identify the ? Discontinue drugs when no indication Strive for a diagnosis before treatment Review ? Start with low dose, titrate up slowly, and use lowest effective dose Use the fewest possible number of drugs the patient needs Use new agents cautiously Consider non-pharmacological treatment Screen for ? interactions Assess medication adherence Inquire about previous? Avoid the ? Identify ? Evaluate laboratory findings Renal function Hepatic function Therapeutic drug monitoring (e.g., digoxin, warfarin, phenytoin) Therapeutic goals for chronic disease - Titrate drug dosage with patient response - Establishment of clear and reasonable therapeutic endpoints and monitoring plans - Adjust dosage until endpoints are reached or side effects prevent further increases Simplify the? and encourage ? Use medication only when indicated Discontinue unnecessary medications/supplements/herbals Simplify dosing times to minimize complex regimen Tailor regime to individual's daily routine to improve adherence Provide ? education and ? aid Verbal and written information about medications and/or disease states in health care literacy-sensitive manner. Explain why ? Specific product education for non-oral agents (e.g., inhalers, insulins, ophthalmic/otic drops, etc) Medication chart/list to include generic and brand names, indications, doses, direction for use, timing of doses Information on medication storage, expiration date, and refill status Medication organizer (e.g., pill box) when indicated Encourage compliance. Utilizing compliance aids (e.g., pill boxes, medication calendars), and encouraging family support can help to improve medication adherence Recognize any ? or ? barriers that can be overcome (providing nonchild-resistant caps and tablet cutters) Promote self-monitoring and lifestyle modification Use of blood pressure monitoring device and glucose meter. Diet and exercise. Smoking cessation. Immunizations Regularly review the treatment plan, and discontinue drugs no longer needed Medication reconciliation

-medical history -pharmacology of the drugs prescribed -indication for all medications used by the patient -medication doses to determine any under-dose and/or overdose r drug-drug, drug-disease, drug-vitamin/herbal, drug-food -ADRs -"prescribing cascade" -untreated indication or under-treatment - therapeutic regimen, compliance -medication , adherance -the drug is being prescribed -physical or functional -

Predictors for ADRs: -More than four ? -More than four ? -Previous ? -GFR less than ? mL/min -Low ? -Use of certain medications including diuretics, NSAIDs, antiplatelets, and digoxin -More than ?-day hospital stay -General medical unit admission vs. geriatric ward -? use history -Lower Mini-Mental State Examination score (confusion, dementia) -Two to four new medications added during ? Most common ADRs in the elderly: ADRs are an all-too common cause of hospitalization of elderly people. Elderly are more sensitive than younger people to a variety of drugs acting on the central nervous system. Adverse effects of benzodiazepines increase with increasing age and dose. Another example is an association between age, NSAIDs and peptic ulcer disease. Examples for adverse effects of various drugs: Benzodiazepines: ? NSAIDs: ? Opiates: ? Antiarrhythmics: ? Antipsychotics: ? Diuretics: 4? Falls About: 40% of the persons over 85 fall each year. As a result, 5-10% of this group copes with serious injuries like hip fractures. Various studies have investigated the association of drug treatment and falls. ? is an important factor causing elderly to fall. Different drugs can cause this symptom either directly or by inducing dehydration. ? and ? cause orthostatic hypotension and dehydration. ACE inhibitors, β-blockers and diuretics decrease ?, and also cause arterial hypotension. ? drugs are an important risk factor for falls; they even can increase the risk of falling 2-fold. These drugs disturb ?, and cause dizziness, orthostatic hypotension and delayed reaction. Impairment of motor and cognitive skills and ? persists for a period of time after the use of many psychoactive drugs. Withdrawal of psychoactive drugs helps to prevent falls. Double Incontinence: Double incontinence is the inability to perceive, retain and evacuate stool and urine at the time and place of choice. At least 15% of men and women above 75 years of age suffer from double incontinence. Toxicity: In elderly people, some drugs can easily achieve toxic levels. Especially when the drug's therapeutic window between efficacy and toxicity are small.

-prescription medications -active medical problems -ADR -50 -body weight or BMI -14 -Alcohol -hospitalization -sedation, confusion, ataxia. -fluid retention, peptic ulcer. -sedation, confusion, constipation. -confusion, urinary retention. -dyskinesias, rigidity, confusion, sedation. -dehydration, hyponatremia, glucose intolerance, orthostatic hypotension. -Orthostatic hypotension -Diuretics and nitrates -afterload -Psychoactive -balance -tardive dyskinesia

KEY CONCEPTS Population aging is an incontrovertible trend. Older adults constitute a very heterogeneous group ranging from healthy, fit, community-dwelling individuals taking no regular medication to frail institutionalized individuals with multiple comorbidities and polypharmacy. All four components of pharmacokinetics - absorption, distribution, metabolism, and excretion - are affected by aging. The most clinically important and consistent is the reduction of ?. In general, the pharmacodynamic changes that occur in the elderly tend to increase their ? to drug effects. When prescribing drug therapies in older adults, it is important to use the ? required to obtain benefit. Comorbidities and polypharmacy complicate elderly health status, particularly when polypharmacy includes ? that lead to drug-related problems. Older adults are at greater risk for medication non adherence due to the high prevalence of multiple comorbidities, including cognitive deficit, polypharmacy use, and financial barriers. The clinical approach to assessing older adults frequently goes beyond a traditional "history and physical" used in general internal medicine practice. Optimal drug therapy in the older patient should include: An assessment of the aims of therapy in the individual Risks of drug therapy The effect of ? on drug effects Monitoring the drug efficacy and adverse drug effects once drug therapy is initiated Consideration of geriatric patient's vision, hearing, swallowing, cognition, motor impairment, and education and literacy levels during counseling and education can lead to enhanced medication adherence. Long-term care geriatric practices emphasize the interprofessional team approach.

-renal elimination of drugs -sensitivity -minimal dose -inappropriate medications -disease

DRUG-RELATED PROBLEMS (DRPs) POLYPHARMACY Polypharmacy is defined as taking multiple medications concurrently (at least five) or the use of unnecessary medications. It is prevalent in older adults who compose 14% of the U.S. population but receive 36.5% of all prescription drugs. According to the Centers for Disease Control and Prevention, polypharmacy is the primary cause of adverse drug reactions (ADRs) in older adults. INAPPROPRIATE PRESCRIBING: Inappropriate prescribing is defined as prescribing medications that cause a ? when there is an effective and safer alternative. The incidence of prescribing potentially inappropriate drugs to elderly patients has been reported to be as high as 12% in those living in the community and 40% in nursing homes residents. Beers Criteria It was first developed in 1991 as a tool to identify inappropriate drugs or high-risk drugs in the elderly. The new Beers criteria (updated in 2012 by the American Geriatric Society) includes 53 medications or medication classes that are potentially inappropriate in elderly patients. They are divided into three categories: (a) ?, (b) medications to avoid in ?, and (c) medications to use with ?. Its use can enhance clinical judgment in prescribing for older patients, thereby avoiding unnecessary and potentially harmful prescribing cascades. Unique and appropriate way to determine medications to be either discontinued or safely used in geriatric adults. For further information on "Beers Criteria - Potentially inappropriate Medications for Geriatrics use "Geriatric Dosage Handbook - Including Clinical Recommendations and Monitoring Guidelines", 18th Edition Lexicomp, or "Drug Information Handbook - A Comprehensive Resource for all Clinicians and Healthcare Professionals", 22nd Edition Lexicomp. UNDERTREATMENT Underuse of medications, defined as the omission of drug therapy that is indicated for treatment or prevention of disease. ADVERSE DRUG REACTIONS (ADRs) ADR is defined by the World Health Organization as a reaction that is noxious and ?, which occurs at dosages normally used in humans for prophylaxis, diagnosis, or therapy. Common ADRs are 5? More than 95% of ADRs that occur in the elderly are considered predictable, and 50% are considered preventable. In the United States over two million serious ADRs occur annually and account for over 100,000 deaths. ADRs increase with ?. In fact, the relationship between ADRs and the number of drugs is corollary. After 5 prescribed medications, the percentage of patients with ADRs nearly doubles. Once 9 prescription medications are breached, there is a 100% risk of an ADR (Figure 7).

-significant risk of an adverse drug reaction (ADR) -medications that should be avoided regardless of disease/condition; certain diseases or conditions; caution -unintended -over-sedation, falls and fractures, bleeding, hallucinations, and confusion. -polypharmacy

PHARMACODYNAMIC CHANGES Most pharmacodynamics changes in the elderly are associated with a progressive reduction in homeostatic mechanisms and changes in receptor properties. Although the end result of these changes is an increased sensitivity to the effects of many drugs, a decrease in response can also occur (Table 6, Table 7). Therefore, clinicians must 4 things? Table 6: Pharmacodynamics involving these drugs: -Cardiovascular drugs? -CNS drugs? -Anti-coagulants? -NSAIDs? -Fluids and electrolytes ? Table 7 - Changes in Response to Drugs With Aging : -Decreased sensitivity of the ?reflex occurs with aging which changes the cardiovascular response to many drugs. --? receptor antagonists may be less effective in controlling hypertension in the elderly. The acute blood pressure response to ? may be greater in the aged. -Aging increases the sensitivity to many CNS drugs. Older adults are more sensitive to the ? and ? effects of benzodiazepines, and experience more cognitive impairment. Older adults are more sensitive to opiates and general anesthetics. Exposure to any psychotropic medication, regardless of class, is associated with an almost twofold increased risk of ? in older adults. Psychotropic and ? medications are strongly associated with cognitive impairment and delirium in the aged, as well as anticholinergic adverse effects such as urinary retention and postural hypotension, and may reduce the effectiveness of ? therapy in managing Alzheimer disease and related dementias. Antipsychotic drugs increase the risk of drug-induced ? in the elderly which might be misdiagnosed as a new medical condition Clinical Pearl: The most famous adage about pharmacotherapy for geriatric patients is "Start low, and go slow!" When we "start low", the changes in the 3? of an elderly patient are addressed. When we "go slow," the changes in ? are handled

-start medications at low doses and titrate slowly, longer interval between doses, longer periods between changing doses, closely monitoring the patient for any adverse response. -increased instances of orthostatic hypotension -Increased sensitivity overall to these drugs -Increased sensitivity and risk of bleeding -Increased toxicity and renal damage -dehydration, hyponatremia and hypokalemia -baroreceptor -B-Adrenergic -Calcium channel blocker -sedative and respiratory depressant -falls -anticholinergic -cholinesterase inhibitor therapy -parkinsonism -Vd, protein binding, and pharmacodynamics -metabolism and excretion

THE "PRESCRIBING CASCADE" ("PC") what is it? To minimize the risk of PC Assume any new symptom as ? until proven otherwise. Monitor patients for signs or symptoms of ?. Document the expected response to therapy and ? therapy if this goal is not achieved Document the risk and benefit of any medical therapy, but more importantly, justify whether the drug therapy is medically necessary NONADHERENCE Full compliance with therapy is a large problem in elderly people. Noncompliance is the failure to take or administer the medication as prescribed and can be a problem of either underuse or over-use. The most common type of noncompliance is: 6? Factors influencing the inability to adhere with a medication regimen: Three chronic medical conditions More than five prescription medications Twelve medication doses per day Three prescribers involved Significant cognitive or physical impairments (e.g., memory, hearing, vision, color discrimination, child-resistant containers) Living alone in the community Recently discharged from the hospital Reliance on a caregiver Low health literacy Medication cost Demonstrated poor adherence history

A prescribing cascade occurs when the adverse effect of a drug is misinterpreted as a sign or symptom of a new disorder, leading to a new drug being prescribed to treat that effect. This situation is heightened when the new, unnecessary drug causes additional adverse effects, which may then be misinterpreted as yet another disorder and treated unnecessarily (Figure 8). -drug-related -ADRs -discontinue or up titrate -The simply failure of the patient to take a medication The premature discontinuation of a medication Its use at the wrong time Excessive consumption Use of medications not currently prescribed Inappropriate use of OTC medications

Absorption changes with age: -? physiology is chnaged with aging -? is preserrved -unpredictable ?, ? , and ? -? disease or interferance from ? may interfer with absorption Vd and aging: -lean body mass? -body fat? Total body water? Transport and aging: -serum albumin? -when is this relevent? Metabolsim and aging: -Hepatic size Hepatic BF? -Clearance? -Liver cells? -What is preserved? -What is diminshed ? Exrection and aging: -Renal aspects that decrease with aging? -Clinical significannce of decreased renal clearance? -Despite less clearance and renal function, Scr remains normal, why?

GI--> decreased acid, increased emptying time, decreased splanchnic BF, decreased active transport, decreased mobility, decreased surface area -oral absorption -transdermal, subcut, intramusc -GI, food/other medications -decreased skeletal muscle, therefore drugs that typoically deposit there have a higher serum concentration -increased- lipophilic drugs have increased Vd, half life and duration -decreased, hydrophilic drugs have smaller Vd, shorter half life and decreased duration of action -decreased- it can effect serum concentraiton in itially but unless clearance is effected the steady state stays the same for these drugs - if the drug has a narrow theraputic index and the drug concentration gets increased in a hypoalbuminic patient, they could get toxic levels of unbound serum drug decreased -decreased -decreased (for some drugs), bioavauilability is less efective and dose is larger in older people -deecline, less recovery from injury -Phase II -Phase I -Mass, BF, GFR, filtration fraction, secretion -increased halflife, serum concentration, and ADRs- especially for those with low therapeutic threshold- digoxin, lithium, AGs - less creatinine production