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Chapter 5

Chapter 5 discusses the complexities of therapeutic drug monitoring in geriatric patients, highlighting the physiological changes associated with aging that affect drug metabolism and response. It emphasizes the importance of personalized pharmacokinetic considerations when prescribing medications to older adults, as they often exhibit altered drug absorption, distribution, metabolism, and excretion compared to younger individuals. The chapter also addresses the increased risk of adverse drug reactions and drug-drug interactions in the elderly due to polypharmacy and physiological changes, underscoring the need for careful medication management in this population.

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26 views8 pages

Chapter 5

Chapter 5 discusses the complexities of therapeutic drug monitoring in geriatric patients, highlighting the physiological changes associated with aging that affect drug metabolism and response. It emphasizes the importance of personalized pharmacokinetic considerations when prescribing medications to older adults, as they often exhibit altered drug absorption, distribution, metabolism, and excretion compared to younger individuals. The chapter also addresses the increased risk of adverse drug reactions and drug-drug interactions in the elderly due to polypharmacy and physiological changes, underscoring the need for careful medication management in this population.

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Chapter 5 ‘Susan W. Miller Therapeutic Drug Monitoring in the Geriatric Patient ‘The complex proess of aging characterized by progressive loss inthe functional capacities organs, a red tion in mechanisms of homeostasis, and altered response to receptor stimulation. These changes combine 0 tneteae the suscepibiity of elderly individuals to environmental and physial stressors aswell asthe elects tl medications The previlence of diseases increases with advancing age, and ths increase is accompanied by. increase inthe use of medications * Medication therapy i among the most widely used and highly vl- ued interventions for acute and chronic diseases of older adults, yet the use of drug therapy mn the geniatnic patient is one ofthe most iffcult aspects of patent care The unexpected or exaggerated response to dug therapy exhibited by a gevatc pavent compared witha younger patient ofthe same sex and body weight can irequenly be explained through pharmacokinetic or pharmacodynamic changes.” Older patients take more tmedications than younger persons, yet major drug studies are performed primarily on individuals younger than 55 years of age ‘The effects of aging on drag metabolism are complex and difficult to predict. These effects depend on the pathway of drug metabolism inthe liver, on environmental factors, and on cardiac function.* Although many inteversible changes occur with aging, its now well recognized that individuals age at diferent rates (chrono- logical and biological age are not necessarily synonymous). Fralty, a biological syndrome in the geriatric patent, is recognized as a confounding factor when considering the impact of aging on drug disposition. *? The frailty of a geriatric patient can alter drug metabolism, and this effect appears to vary from drug to drug, The frat elderly (hose that ate vulnerable and are atthe highest risk for adverse health outcomes) have been shown to have reduced drug metabolism.’ Frail older adults are identifiable as those at high risk for dependency, institu- tionalization, falls injuries, acute illness, hospitalizations, slow recovery from illness, and mortality” Markers for inflammation, stich as tumor necrosis factor [TNF-a], interleukin-6 [1L_6], and C-reactive protein, may serve as biochemical markers for frailty and may prove to be a method to characterize an individual’ biolog}- cal age. Because of the frailty of elderly patients, iis important that the first medication prescribed be the ‘most effective choice forthe best chance at an optimal clinical outcome." To make the most effective choice clinicians should take into consideration both personalized pharmacokinetic changes in drug metabolism and pharmacodynamic responses of individual patients, when selecting drug therapies for geriatric patients, Pharmacokinetic studies comparing young and older adults are often difficult to accomplish due to the problems associated with recruiting healthy older individuals to compare with healthy younger individuals, however they are increasing in number." Problems have been identified withthe selection of patient partici- pants and reporting ofthe results of cinical trials to assess age-related pharmacokinetic differences in drugs ® Often, participants are the healthy (younger) geriatrics and not the very old (over the age of 85 and/or frail) geriatric patients, The extrapolation of dosages and possible side elfcts in the very old population may or may rot be appropriate* Physiological dillerences, pathophysiological changes, altered protein binding, and/or concomitant tse of medications may account for the altered pharmacokinetics displayed by older patients ® The following examples illustrate the variability of changes that occur in the elderly. There is evidence to show that increased age may delay absorption of transdermal opioids, but not affect the maximum and steady state concentrations. " An infusion of morphine into older patients showed a rapid distribution, followed by 4 slower elimination when compared to younger patients." Recent pharmacokinetic studies have reported no reed for dosage changes in the elderly for proton-pump inhibitors, or 3-hydlroxy-3-methylglutaryl-coenzyme ‘A(HMG-CoA) reductase inhibitors." Data shows that the angiotensin converting enzyme inhibitors trandol ‘prl and moexipn! should be initiated at lower doses in geriatric patients, but no overall dosage modifications fare necessary." Other data shows that, in the presence of renal impairment, plasma concentrations of ACEIs increase and doses should be adjusted based on renal function.” The SERMS (selective estrogen receptor modu- 6 46 Closica Pharmacokinetics lators) have variable pharmacokinetic changes associated with aging, with tamoxifen and toremifene exhibiting increased plasma concentrations with increased age; tamoxifen greater than toremifene: however, nether drug, has accompanying package insert recommendation for dosage alterations. No age-related differences in raloxt Jene pharmacokinetics have been identified, but cautionary dosing is advised in both moderate-to-severe renal impairment and in hepatic impairment. Nonsteroidal ant-inflammatory drugs (NSAIDs) exhibit reduced renal clearance inthe presence of renal impairment.” Decreased clearance and prolonged hall-ife of sertraline suggest that steady’ state concentrations would be higher and achieved later during long-term administration to geriatric patients ® A reduced clearance for [Link], and ropnirole has been shown in genatric patients, with the clinical significance ofthis reduced clearance unknown.*'*" The fluoroquinolone antibacterials, including ciprofloxacin, and levofloxacin require dosage adjustments based on their predominant renal elimination. The antiepileptic drugs, felbamate, ‘gabapentin, lamotrigine, levetiracctam, axcarbazepine, tagabine, and topiramate, all exhibit a decrease in appar ent oral clearance in elderly patients when compared to non-elderly adult controls” Studies measuring the pharmacokinetics of the cholinesterase inhibitors tacrine, danepel, vastgmine, and galantamine in genatric Patients report some changes in pharmacokinetic parameters, but these ae not considered clinically significant and no dosage changes are suggested unless patents are in severe renal impairment (galantamine and creat rine clearance <9 mi'min).* Due to hepatic toxicity lacrine and galantamine are not recommended for use in patients with severe hepatic impairment." Information regarding dosage aterations based on the pharmacokinetic profiles of drugs in geriatric patients 's very important tothe clinician as current dosing in gertatric patents is often based on broad generalzations such as “use one third to one half the usual dose,” or anecdotal data—not on sold pharmacokinetic or phar- rmacodynamic studies. Pharmacokinetic and/or pharmacodynamic diferences in older patients may account for either the tonic or subtherapeutie response that often occurs. Adverse drug reactions or events (ADEs) and drug-druginterations (DDIs) occur more frequently in geriatric Patients, n part because this population is most likely to be using complex drug therapies “"> The estimated annual rate of ADEs for individuals aged 65 years or older has been measured at more than twice the rate for those younger than 65 years of age.” Additional data has shown that for persons 65 years of age and older, the estimated annual rate of ADEs requiring hospitalization was nearly seven times the rate for persons younger than 65 years. Although considerable evidence suggest that an ADE will not occur simply because a patent is elderly, pharmacokinetic and pharmacodynamic changes in the elderly may significantly alter drug disposi- tion and must be considered as contributing to ADEs.”»” Symptoms of ADEs can be extremely subtle in an elderly patient and may be manifested by increased frequency of falls, increased confusion, excessive sedation, constipation, urinary retention, decreased oral intake, or a general failure to thrive. * Significant ADES are most likely observed with drugs having a narrow therapeutic index or saturable he- patic metabolism (eg, phenytoin, warfarin, and theophylline) or when elimination is via a single mechanism or pathway A study of emergency department visits for ADEs showed that drugs that commonly require regular ‘outpatient monitoring to prevent toxicity (antidiabetic agents, warfarin, several anticonvulsants, digitalis giyco- sides, cheophyltine, and lium) were involved in the most unintentional overdoses. The patients most at risk usually have multiple disease states or compromised organ function, and they receive multiple drug therapy. ‘Complicated drug therapy, poor compliance, and altered pharmacokinetics are among the many possible causes of ADEs and DDIs. "927° Physiologic Changes Absorption, distribution, metabolism, and excretion ‘The processes of absorption, distribution, metabolism an excretion determine the amount of drug present at any given time within the bodys various tssue and fh compartments Pharmacokinetic parameters represent a composite of both genetic and environmental effects The physiologic changes produced by aging that may have imponant implications for altered pharmacokinetics are sumnmanzed in Table 5-1 Age-related physiologic changes nthe gastrointestinal (GD trac include elevated gastric pH, delayed gastn emptying, and decreases in GI motliy, intestinal blood flow, and absorptive surlace area Reduced gastric secretion of acid can reduce tablet dissolution and decrease the solubility of asic drugs Therapeutic Dug Montorng inthe Gert Patent 47 Table 5-1. Physiologic Changes with Aging that May Affect Pharmacokinetics* Process Physiologic Effect ‘Absopion| Reduced gastic acd poducton Reduced gas rptyng rate Rtuced Gl oatty Reduced Gl toad flow Reduced absorptive sutace Distibwtion Decreased total body mass Irereased percentage of boy fat Decreased percentage of body water Decreased pasa albumin Disease ated rrease [Link] gheopoton ‘Atered rele issue person ‘Aered poten bing Metabolism Reduced iver mass Reduced let ood ow Feducedhepate metabo capacity duced erayme atwty Reduced enzyme ncn Becton Reduced rel lod ow Reduced goer latin Aeduced rel ubuor secretary function Tasve senstiy Ateratons in eceptor uber ‘Aeraton in ecepirafinty ‘Ateratons in second messenger functnt ‘erations cellar response ‘Aeratons cel nucle response {Reema eg, A or") made he aep oo le meng enamel pardons mp of “The delay in gastric emptying allows more contact time in the stomach for + Potentially ulcerogenic drugs such as the NSAIDs and bisphosphonates, ‘+ Antacid drug interactions due to an increased opportunity for binding, + Increased absorption of poorly soluble drugs Ahigher incidence of diarthea and a delay in onset action of weakly basic drugs also result from this physt- logic effec. ‘One study reported a three-fold decrease in levodopa availability in the elderly because delayed gastric emptying allowed the increased degradation by GI dopa-decarboxylase to dopamine.” Differences in gastric emptying might help explain the unpredictable and inconsistent responses to levodopa in individual patients." ‘The increased degradation of levodopa by dopa-decarboxylase occurs when levodopa is used alone (not in combination with a dopa-decarboxylase inhibitor such as carbidopa). Levodopa is only used in combination, therapy as an anti-Parkinson’ agent CClorazepate, a benzodiazepine, is converted by acid hydrolysis in the GI tract to an active metabolite, ddesmethyldiazepam. Desmethyldiazepam concentrations have been reported to be lower in both elderly and gastrectomized patients compared with younger adults. This decrease in active metabolite levels is presumed to bea result of a decreased conversion from the parent drug.” ‘Age influences the active transport mechanisms involved in the absorption of nutrients such as sugars, vitamins e ,,thiamine and folic acid), and minerals (e.g, calcium and iron). In elderly patients, this absorption is often reduced Age-related physiologic changes alone apparently do not influence the passive transport ‘mechanisms by which most drugs are absorbed. Some drugs with high intrinsic clearance inthe liver are metabolized during thelr passage from the portal vein through the liver to the systemic ciculation, thus reducing thei oral bioavailability, Drugs with poten aly increase oa in the elderly presumably due toa decrease in first-pass metabolism, are shown 48 Clinical Pharmacokinetics Drugs that undergo first-pass metabolism and may have decreased bioavailability in older patients include lorazepate, digoxin, and prazesin.” The decrease in bioavailability may be the result of a combination of reduced blood flow to the hepatic system and slowed GI motility that allows for drug degradation in the GI tract prior to absorption Although the total amount of absorbed drug reaching the systemic circulation is affected for only a few drugs, age-related physiologic changes can alter the absorption rate, resulting in an erratic and sometimes inconsistent pharmacologic response. The clinical effect of this is a delay in the time to peak or maximum concentration, which is more problematic with therapies where a high peak or short time to peakis important. Clinical factors such as acute congestive heart failure (CHF), achlorhydria, and unusual dietary patterns may ‘occasionally necessitate the intravenous route of administration because ofthe incomplete absorption via oral and intramuscular routes. The absorption of intramuscularly administered drags decreases in bedridden elderly patient, perhaps because of changes in regional blood flow: In geriatric patients, percutaneous absorption of transdermal medications can be affected by reductions in the water and lipid layers of the aged skin. Lipophilie ‘medications such as testosterone, estradiol, and fentanyl have shown reduced absorption in geriatric patients.” Considerations involved in using controlled-release dosage formulations include age-related changes in Gl transit time, motility. and pH. Binding proteins Agecan alter the distribution of drugs throughout the body and to target organs. Although total protein gener- ally is unaffected by aging, the plasma albumin portion has been shown to decrease from 4 g/dl in young adults to approximately 3.5 g/l in patients over 80.” The mean serum albumin of nursing facility residents has been found to be 3.0 g/l or lower. The two major plasma proteins to which medications can bind are albumin and alpha-1-acid glycoprotein (AAG), and concentrations ofthese proteins may change with concurrent pathologies seen with increasing age. Plasma protein binding is a major determinant of drug,action, particularly for drugs that are highly protein bound and changes in protein binding can have clinical implications.» If albumin is decreased, a compensatory increase in unbound (active) drug occurs ifthe percentage of the bound drug is {90% or more; however, this is often compensated by increased distribution or clearance, so litle or no clinical cflect is experienced. In addition to age, disease states such as cirrhosis, renal failure, and malnutrition can lower albumin concentrations, |AAG, an acute phase reactant, binds mostly to lipophilic basic drugs and tends to increase with age and in response to acut illness. The binding of drugs to AAG increases during acute illness and can return to normal after several weeks of months when the acute stress passes and AAG decreases.” Medications that bind to AAG and are commonly associated with adverse effects in geriatric patients are lidocaine, meperidine, and propranolol” Though protein binding may be altered in aging, physiological changes and pathophysiological disorders also occur and these changes usually have greater clinical significance than changes in drug plasma protein binding.” Increased unbound (free) fraction Increases inthe fiee Fraction of naproxen, diftunisal, and salicylates have been found in the elderly, presumably asa result ofthe decrease in albumin protein binding.” Increased concentrations of NSAIDs have been associ- ted with a higher incidence of gastric bleeding from peptic ulcers" Whether the increas in gastric bleeding {is due to changes in protein binding or the increased drug concentration is not known, Table 5-2. Drugs with Increased Bioav: ity in the Elderly ‘Amine Ticaine Cherdarepoe ‘Metopoa Cimeisne Metoidaoe Desiamine Roprandiol Imipramine Ouiisine Labetl Trarodone Leveson Verapamt Therapeutic Drug Monitoring inthe Gea Patient 49 Decreased protein binding (as well as the resultant increased free fraction) is also seen with phenytoin, which {s cleared from the plasma more rapidly because of an increase in free phenytoin.” Seizure control may be seen at lower measured total (bound plus unbound) phenytoin concentrations in the elderly whose unbound frac- tion has increased. Although the increase in the fre fraction of phenytoin with age is statistically significant, iis unlikely to warrant a compensatory change in dose unless the patient has a total phenytoin concentration that is near the upper limit of the therapeutic range and/or that is sufficient to saturate metabolizing enzymes. With meperidine, binding to red blood cells decreases with age, thus increasing the amount of free meperidine available in the elderly patient." Meperidine is considered an inappropriate drug for use in the elderly» ‘Although higher concentrations and the resulting therapeutic effects of some drugs may be beneficial, the accompanying risks of toxicity are problematic in the geriatric patient. Doses of most highly protein-bound drugs (>90% protein bound) should be reduced initially and increased slowly if there is evidence of decreased serum albumin (i.e., <3.5 g/dl). If several highly protein-bound drugs are used together, the chance of a drug interaction increases. Table 5-3 shows the impact of age on the protein binding of select drugs. Lean body weight to fat ratio ‘Changes in the ratio of lean body weight to fat also can alter drug distribution leading to changes in pharma- cologic response. In the average elderly patient, total body water is decreased and total body fat is increased These changes influence the onset and duration of action of highly tissue-bound drugs (¢.g.. digoxin) and ‘water-soluble drugs (e.g, alcohol, lithium, and morphine). The dosages of most water-soluble drugs are based on estimates of lean or ideal body weight. Ifa patients actual weight is less than the estimated lean body weight, the actual weight should be used in mast dosage calculations, Between ages 18 and 85, total body fat increases on average in both females and males; lean body mass even tually decreases in both groups as well. With increasing age, the volume of distribution of lipophilic drugs may increase as a result of diminished protein binding and an increased fat to lean muscle ratio, Fat-soluble drugs (e.g, most tricyclic antidepressants, barbiturates, benzodiazepines, calcumn channel blockers, and phenothiazines) may have a delayed onset of action and can accumulate in adipose tissue, prolonging their action sometimes to the point of toxicity®” ll of these drugs are considered inappropriate in the elderly due to safer alternatives.**** Drug Elimination Drugs are primarily cleared from the body by metabolism in the liver, excretion by the kidneys, or some com- bination of the two processes. A decrease in total body clearance results in higher drug concentrations and an ‘enhanced pharmacologic response, which can lead to toxicity.®* Metabolism For some drugs, hepatic metabolism is highly dependent on blood flow. Liver blood flow can decrease sig- nificantly with increasing age and is further compromised in the presence of congestive heart failure (CHF). ‘With drugs that are highly dependent on hepatic metabolism (e.g., most beta-blockers, lidocaine, and narcotic analgesics), a decrease in hepatic clearance can increase the drug concentration and lead to toxicity In addition to altering hepatic blood flow, age influences the rate of hepatic clearance by causing changes in the intrinsic activity of selected liver enzymes. This age-related process has been found in the Phase I enzy- ‘matic pathway. Common drugs using this pathway and having the potential for metabolism influenced by age include the longer acting benzodiazepines such as diazepam, chlordiazepoxide, and clorazepate. The enzymatic demethylation of nortriptyline ** imipramine,” thioridazine. and theophylline" also decreases in the elderly. All of these drugs are considered inappropriate for use inthe elderly except imipramine" Drugs that undergo hepatic Phase It enzymatic biotransformation (e.g. lorazepam, axazepam, and temazepam) do not appear to be adversely affected by age; therefore, they are preferred agents for older patients. At all ages, drug metabolism can be affected by genetics, smoking, diet, gender, comorbid conditions, and concomitant drugs. The cytochrome P (CYP) 450 enzyme system, primarily a part of the Phase I hepatic ‘metabolism pathway, can be affected by many drugs. Of the more than 30 CYP 450 isoenzymes identified to date, the major ones responsible for drug metabolism include CYP3A4, CYP2D6, CYPLA2, and the CYP2C subfamily: Newer evidence in geriatric patients has shown a reduction in CYP2C19 activity, no reduction in 50. Clinical Pharmacokinetics Table 5-3, Effects of Age on Plasma Protein Binding of Select Drugs in Geriatrics ‘Drugs with decreased protein binding (increased fee fraction) ‘Acetaolamide? Lorazepam Carbenoxalone Meperidine Ceftiaxonea Naproxen Clomethiacle Phonytia? Desipramine? Saliyatet Desmethyiazepam Temazepam Diazepam Theoptyiline Difnisal Tobutanide Fuphenarine Tiaoam® Flurazepam Waternt lidecanet Drugs with increased protein binding (decreased free faction) Amivigtyinet* Flurazepam Berazeptiat Haloperid Ceftriaxone’ Ibuprtent Chlorpromazine? Lidoeines Clomeshiazolet Naproxen Disopyramide” Nestptyine! Enaapiat Propranala* Exomidate Select drugs with no change in protein binding Abrazolam Metopolot Amitiptyines* Midaalan Atropine Nadool Cateine Nitvazepam? Oxazopam Nostpyine Chloréazepoxide Ponca Chloroguine Phencbarital Desipraine’ Phenytint Desmethyliazepam Proxicam Diazepam Proprarala Disopyramide’ Ouiidne Donepei Risperidone Erodlac Sali Fentanyl Sota Furosemide Saladiane Haloperid Sutamethoxarole Ibupeoent Thiaridaxine? Imigraine Tiazolan Lorazepam? “Timethopsim Maproiine Yancamycin Meperidine! Verapamil Methadone Wart Methotrexate ‘Therapeutic Dug Menitring in the Geriatric Patint 81 C¥P2DG activity, and marked variability with litle change in the CYPLA2, CYP2C9, CYPZEL, and CYP3A+ isoenzymes.""®” CYPs are increasingly being identified in extrahepatic organs such as the intestine, kidney, brain, and skin. The full effect of aging on these enzyme systems is yet to be determined.” Unlike renal function, no accurate laboratory tests directly measure liver function for drug dosage adjustment. Nonspecific tests to monitor liver function include ALT, plasma albumin, and prothrombin time. Renal clearance Consistent with the behavior of many drugs, pharmacokinetic data from elderly patients are similar to that of patients with mild renal compromise, in that most age-related declines in drug clearance can be explained by reductions in renal function.”* Age-related physiologic changes in the kidneys influence drug response and climination more than hepatic changes in the geriatric patient. Between ages 20 and 90, the glomerular filtra- tion rate (GFR) may decrease as much as 50% (average decline of 35%). The average CrCl of elderly nursing facility residents has been found to be about 40 mV/min.” Serum creatinine is frequently used to monitor kidney function, but this test alone is of limited utility in estimating the GFR of the geriatric patient. Serum creatinine does not increase significantly unless kidney function deteriorates greatly. The production of creatinine, which is dependent on muscle mass, decreases in the elderly; therefore, an apparently normal serum creatinine in a ‘geriatric patient may not be a valid predictor of renal function and drug elimination, Blood urea nitrogen (BUN) also is nota useful predictor of renal function because it can be affected by hydration status, diet, and blood loss, ‘The most accurate, readily available estimation of GFR in the elderly is creatinine clearance (CrCl), which correlates well with both GFR and tubular secretion. The CrCl can be estimated using a standard equation that considers age, body weight, and serum creatinine in patients with stable renal function (see Chapter 1). Of ‘course, mathematical equations are simply estimates of an individuals actual renal function. Even the best meth- ds for estimating creatinine clearance may result in suboptimal dosing for many elderly patients. For geriatric patients with low serum creatinine

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