farmacoterapia adulto mayor -...

FARMACOTERAPIA��

ADULTO MAYOR�

Dr. Carlos Fernando Estrada GarzonaDepartamento de Farmacología

Universidad de Costa Rica

OBJETIVOS } FISIOLOGIA DEL

ENVEJECIMIENTO} FARMACOCINETICA-FARMACODINAMIA

} PRESCRIPCION RACIONAL

FISIOLOGIA DEL

ENVEJECIMIENTO

cells, nerve fi bers, and vestibular ganglion cells affects the vestibulo-ocular refl ex. Decreased mechanoreceptor density and sensitivity and decreased peripheral nerve conductivity decrease vibrotactile sensation.30 In addition, decreased tactile and proprioceptive sensation has also been reported.

SUMMARY

Aging as a physiological process is associated with complex changes in all organs, and these changes occur at varying rates (Table 203-2). They affect the body’s functional

reserve, leading to impaired ability to maintain homeosta-sis and withstand stressors. Awareness of these physiologi-cal changes is an integral part of any comprehensive evaluation of the older patient.

R E F E R E N C E S

1. Knapowski J, Wieczorowska-Tobis K, Witowski J. Pathophysiology of ageing. J Physiol Pharmacol 2002;53:135-146.

2. Lakatta EG, Levy D. Arterial and cardiac aging: Major shareholders in cardio-vascular disease enterprises. Part II: The aging heart in health—Links to heart disease. Circulation 2003;107:346-354.

3. Tsuji H, Larson MG, Venditti FJ Jr, et al. Impact of reduced heart rate variability on risk for cardiac events. The Framingham Heart Study. Circulation 1996;94:2850-2855.

4. Tsuji H, Venditti FJ Jr, Manders ES, et al. Reduced heart rate variability and mortality risk in an elderly cohort. The Framingham Heart Study. Circulation 1994;90:878-883.

5. Furberg CD, Psaty BM, Manolio TA, et al. Prevalence of atrial fi brillation in elderly subjects (the Cardiovascular Health Study). Am J Cardiol 1994;74:236-241.

6. Lakatta EG, Levy D. Arterial and cardiac aging: Major shareholders in cardio-vascular disease enterprises. Part I: Aging arteries—A “set up” for vascular disease. Circulation 2003;107:139-146.

7. Franklin SS, Gustin WT, Wong ND, et al. Hemodynamic patterns of age-related changes in blood pressure. The Framingham Heart Study. Circulation 1997;96:308-315.

8. Campbell E. Physiologic Changes in Respiratory Function. New York: Springer-Verlag, 2001.

9. Rowe JW, Andres R, Tobin JD, et al. The effect of age on creatinine clearance in men: A cross-sectional and longitudinal study. J Gerontol 1976;31:155-163.

10. Adkins R, Marshall B. Anatomic and physiologic aspects of aging. In Adkins R, Scott H (eds). Surgical Care for the Elderly, 2nd ed. Philadelphia: Lippincott-Raven, 1998.

11. Astor FC, Hanft KL, Ciocon JO. Xerostomia: A prevalent condition in the elderly. Ear Nose Throat J 1999;78:476-479.

12. Schulman C, Lunenfeld B. The ageing male. World J Urol 2002;20:4-10.13. Perry HM 3rd. The endocrinology of aging. Clin Chem 1999;45(8 Pt

2):1369-1376.14. Sirota DK. Thyroid function and dysfunction in the elderly: A brief review. Mt

Sinai J Med 1980;47:126-131.15. Haden ST, Brown EM, Hurwitz S, et al. The effects of age and gender on para-

thyroid hormone dynamics. Clin Endocrinol (Oxf) 2000;52:329-338.16. Bilezikian JP, Silverberg SJ. Parathyroid hormone: Does it have a role in the

pathogenesis of osteoporosis? Clin Lab Med 2000;20:559-567, vii.17. Van Cauter E, Leproult R, Plat L. Age-related changes in slow wave sleep and

REM sleep and relationship with growth hormone and cortisol levels in healthy men. JAMA 2000;284:861-868.

18. Smolander J. Effect of cold exposure on older humans. Int J Sports Med 2002;23:86-92.

19. Barbieri M, Rizzo MR, Manzella D, Paolisso G. Age-related insulin resistance: Is it an obligatory fi nding? The lesson from healthy centenarians. Diabetes Metab Res Rev 2001;17:19-26.

20. Kohrt WM, Kirwan JP, Staten MA, et al. Insulin resistance in aging is related to abdominal obesity. Diabetes 1993;42:273-281.

21. Cefalu WT, Wang ZQ, Werbel S, et al. Contribution of visceral fat mass to the insulin resistance of aging. Metabolism 1995;44:954-959.

22. Coffey CE, Lucke JF, Saxton JA, et al. Sex differences in brain aging: A quantita-tive magnetic resonance imaging study. Arch Neurol 1998;55:169-179.

23. Mouton PR, Martin LJ, Calhoun ME, et al. Cognitive decline strongly correlates with cortical atrophy in Alzheimer’s dementia. Neurobiol Aging 1998;19:371-377.

24. Leenders KL, Perani D, Lammertsma AA, et al. Cerebral blood fl ow, blood volume and oxygen utilization: Normal values and effect of age. Brain 1990;113(Pt 1):27-47.

25. D’Esposito M, Deouell LY, Gazzaley A. Alterations in the BOLD fMRI signal with ageing and disease: A challenge for neuroimaging. Nat Rev Neurosci 2003;4:863-872.

26. Groschel K, Terborg C, Schnaudigel S, et al. Effects of physiological aging and cerebrovascular risk factors on the hemodynamic response to brain activation: A functional transcranial Doppler study. Eur J Neurol 2007;14:125-131.

27. Ship JA, Pearson JD, Cruise LJ, et al. Longitudinal changes in smell identifi ca-tion. J Gerontol A Biol Sci Med Sci 1996;51:M86-M91.

28. Anstey KJ, Luszcz MA, Sanchez L. A reevaluation of the common factor theory of shared variance among age, sensory function, and cognitive function in older adults. J Gerontol B Psychol Sci Soc Sci 2001;56:P3-P11.

29. Valentijn SA, van Boxtel MP, van Hooren SA, et al. Change in sensory function-ing predicts change in cognitive functioning: Results from a 6-year follow-up in the Maastricht Aging Study. J Am Geriatr Soc 2005;53:374-380.

30. Verrillo RT. Age related changes in the sensitivity to vibration. J Gerontol. Mar 1980;35:185-193.

TABLE 203-2 Summary of the Physiological Changes That Occur with Aging

ORGAN OR FUNCTION SYMPTOMS ASSOCIATED WITH AGING

Arteries Atherosclerosis, intimal thickening, higher blood pressure, increased risk of cardiovascular disease

Bladder Weakened connective tissue, reduced capacity to store urine, reduced efficiency of bladder emptying

Body weight Declining weight between ages 55 and 75 yr, due mostly to loss of lean tissue, muscle mass, water, and bone

Bones Accelerated loss of bone cells beginning at about age 35 yr; bones become porous and brittle in the demineralizing process

Brain Gradual loss of brain tissue, slower reaction, deterioration in memory, insomnia

Ear Gradual loss of the ability to hear higher frequencies, starting at about age 30 yr

Endocrine Reduced estrogen (females), reduced testosterone (males), reduced GH and IGF1, increased insulin resistance

Fat Increased storageHeart Increased thickness of LV wall, reduced

number of pacemaker cells, increased myocardial stiffness, and reduced compliance.

Immunity Reduced ability to combat infection, increased autoimmune responses

Joints Reduced synovial fluid, increased risk of osteoarthritis, destruction of cartilage, less resilience of tendons, and ligaments

Kidneys Reduced weight and volume of the kidneys, marked reduction in functional ability, loss of nephrons, changes in electrolyte absorption and secretion

Lungs Loss of elasticity and capacity, increasing difficulty oxygenating blood

Nose Declining ability to smell after age 65 yr; amount of reduction varies widely among individuals

Prostate Reduced semen making after age 60 yr; enlargement in size may cause difficulty with urination

Reaction time Slower mental and physical responses to specific stimuli

Thermoregulation Impaired capacity for coping with changes in environmental temperature

Tongue Gradual decline in sense of tasteTumors Increased risk of malignancies

GH, growth hormone; IGF1, insulin-like growth factor 1; LV, left ventricular.

Biology and Physiology of Aging C H A P T E R 203 1129

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1124 S E C T I O N D Geriatrics

P A R T Iv P A L L I A T I V E C A R E A N D G E N E R A L M E D I C I N E

Aging results from a gradual amassing of faults in the cells and tissues that contribute to an increased risk of chronic disease and death.

TWO TYPES OF THEORIES OF AGING (Table 203-1)

1. Programmed theories (intrinsic): emphasize that aging follows a biological timetable, perhaps a con-tinuation of the one that regulates childhood growth and development.

2. Error theories (extrinsic or “stochastic”): empha-size environmental assaults to biological systems that gradually cause things to go wrong.

Aging is characterized by a gradual decline in organ function reserves, which reduces their ability to maintain homeostasis, especially under stress. In many organs, function loss begins at 30 to 40 years of age and proceeds at a rate of approximately 1% annually.1 Although this decline appears continuous and irreversible, aging itself does not mean pathology. Without additional pathogenic stimuli, it will not lead to overt disease. Age-related changes pave the way for disease. Aging without disease is often referred to as “normal” or “physiological” aging. In con-trast, aging associated with disease is called “abnormal” or “pathological” (Fig. 203-1).

CARDIOVASCULAR SYSTEM

Normal physiological changes occur in the cardiovascular system with advancing age. These changes affect both the structure and the function of the heart as well as the arte-rial system (Fig. 203-2).

TABLE 203-1 Theories of Aging

SUBTHEORY EXPLANATION

PROGRAMMED THEORIES (INTRINSIC)

Programmed longevity Aging results from sequential switching on and off of certain genes, with senescence defined as the time at which age-associated deficits are manifested.

Endocrine theory Biological clocks act through hormones to control the pace of aging.

Immunological theory A programmed decline in immune system function leads to an increased vulnerability to infectious disease, aging, and death.

ERROR THEORIES (EXTRINSIC)Wear and tear Cells and tissues have vital parts that wear

out.Rate of living The greater the organism’s rate of oxygen

basal metabolism, the shorter its life span.Cross linking An accumulation of cross-linked proteins

damages cells and tissues, slowing down bodily processes.

Free radicals Accumulated damage caused by oxygen free radicals causes cells, and eventually organs, to stop functioning.

Somatic DNA damage (genetic mutations)

Genetic mutations occur and accumulate with increasing age, causing cells to deteriorate and malfunction. In particular, damage to mitochondrial DNA might lead to mitochondrial dysfunction.

Physiological functions in subjects older than 65 years of age

Vital lu

lood f

Restin

diac i

Glomer

ular f

iltrati

d flow

Intimal hyperplasia

LV ejectionfraction preserved

LV wallthicknessincreases

Reduced pacemaker cells

Superiorvenacava

Right atrium

Pulmonarysemilunarvalve

Aortic valve

Tricuspid valve

Right ventricle

Inferior vena cava

Pulmonary arteryAorta

Left atrium

Pulmonaryveins

Mitral valve

Leftventricle

FIGURE 203-1 Relationship between age and selected functional parameters. (From Knapowski J, Wieczorowska-Tobis K, Witowski J. Pathophysi-ology of ageing. J Physiol Pharmacol 2002;53:135-146.)

FIGURE 203-2 Cardiovascular changes with advancing age. LV, left ventricular.

Cardiac Structure

Cross-sectional echocardiography indicates that left ven-tricular (LV) wall thickness increases progressively with age, in both males and females, independent of cardiovas-cular risk factors.2 There is a progressive loss of myocytes in both ventricles, with a reciprocal increase in myocyte volume. The aging heart has lower myocardial mass due to myocyte cell loss and reactive hypertrophy of the spared myocytes. An increase in the amount and a change in the physical properties of collagen also occur. The

Vital lu

lood f

Restin

diac i

Glomer

ular f

iltrati

d flow

Intimal hyperplasia

Superiorvenacava

Right atrium

Aortic valve

Tricuspid valve

Right ventricle

Inferior vena cava

Left atrium

Pulmonaryveins

Mitral valve

Leftventricle

Cardiac Structure

number of collagen fi bers increases and nonenzymatic cross-linking also increases. The myocyte-collagen ratio remains relatively unchanged, mainly because of increased myocyte size; as a result, hypertrophy rather than hyper-plasia is more prominent in elderly persons. These changes increase myocardial stiffness and decrease compliance. With age, the number of pacemaker cells in the sinus node decreases.

Cardiac Function

The LV early-diastolic fi lling rate progressively decreases to 50% of the peak by 80 years of age. Despite slower LV fi lling in early diastole, more fi lling occurs in late diastole, due partly to a more vigorous atrial contraction, which produces an exaggerated A wave. This is accompanied by atrial hypertrophy and enlargement that is evident on auscultation as a fourth heart sound (atrial gallop). The LV end-diastolic volume does not reduce with age, but it does mildly increase while at rest and during upright exercise.

LV ejection fraction is the most common clinical measure of LV systolic function, and it is preserved. However, the maximum LV ejection fraction (the ejection fraction achieved during exhaustive upright exercise) decreases because of a dramatic reduction in ejection frac-tion reserve during aging. The net result in end-diastolic volume and end-systolic volume regulation during exer-cise is that the stroke volume index (SVI) is preserved over a wide performance range because of a greater use of the Starling mechanism.

The resting heart rate (HR) does not change with age, but the maximal achievable HR decreases; the maximal HR that an 85-year-old can achieve is about 70% of that of a 20-year-old.2 Because the stroke volume does not change over time, the maximal cardiac output (stroke volume × HR) deceases, so the overall cardiac reserves diminish with age. The dysfunction of sympathetic modulation of the cardiovascular system with advanced age is consistent with increased spillover of catecholamine and impaired responses to α-adrenergic receptor stimulation.2 This further reduces myocardial contractility. Aging also affects the LV afterload and vascular-ventricular load matching. This mismatch impairs LV elasticity (contractility) in response to increased afterload. In addition, diastolic pres-sure decreases with age, compromising myocardial perfu-sion and worsening overall cardiac function.

Beat-to-beat fl uctuation of HR, or HR variability, is an indirect measure of autonomic function and declines steadily with age. Reduced HR variability predicts increased risk for subsequent cardiac events3 but also increased risk for all-cause mortality.4 The risk of atrial fi brillation dra-matically increases with age; it is present in 3% to 4% of healthy volunteers older than 60 years of age, a percent-age 10-fold greater than in the general adult population.5

Arterial Tree

Normal aging also affects the arterial system. Intimal hyperplasia and thickening, with decreased vascular com-pliance and increased stiffness, develop with advanced age. The intimal thickness of the carotid artery increases twofold to threefold between the ages of 20 and 90 years.6

Increased nonenzymatic collagen cross-linking is seen, similar to that observed in the myocardium. The elastin content in the media decreases with age. This decreases vascular elasticity (compliance) and increases stiffness. Dysfunctional endothelial vascular smooth muscle tone contributes to stiffer arterial walls independent of athero-sclerotic changes.

The two main determinants of arterial blood pressure are peripheral vascular resistance and central artery stiff-ness. Increases in peripheral vascular resistance increase both systolic and diastolic pressure; central artery stiffness increases systolic pressure but reduces diastolic pressure.6 Blood pressure in younger individuals is primarily dictated by peripheral vascular resistance, but with aging, central arterial stiffness becomes the main determinant of pres-sure.6 Systolic blood pressure increases in adults of all ages, well into the 80s; diastolic pressure peaks in the 50s and then declines.7 The most common hypertension in adults older than 50 years of age is isolated systolic hyper-tension. After allowing for hypertension, the overall effect of aging is higher systolic pressure and decreased diastolic pressure, manifested as a widened pulse pressure.

RESPIRATORY SYSTEM

The chest wall becomes increasingly rigid with advancing age. This, together with reduced respiratory muscle strength, increases closing capacity and decreases forced expiratory volume in 1 second (FEV1). The partial pressure of oxygen also decreases progressively with age, due to a combination of age-induced mismatch between ventila-tion and perfusion, diffusion block, and anatomical shunt. This decrease becomes more prominent during exercise. Hypoxic and hypercapnic ventilatory drives also diminish with age. The large airways grow slightly with age, leading to more dead space.8 The respiratory bronchioles and alveolar ducts increase in size signifi cantly, particularly after age 60 years. The fraction of lung consisting of alveo-lar ducts also increases progressively over time. The cumu-lative surface area for gas exchange decreases by 15% by 70 years. There is progressive loss of diffusing capacity and elastic recoil with advancing age. This is mainly caused by the fusion of adjacent alveoli, which decreases surface tension forces and pulmonary elastic recoil.8 In addition, chest wall stiffness increases with advancing age, causing a decrease in compliance. This results from a combination of factors: calcifi cation of intercostal cartilages, arthritis of the costovertebral joints, and gradual atrophy and weak-ening of the intercostal muscles. With increasing age, the intercostal muscles gradually begin to atrophy and weaken, so breathing requires more from the diaphragm and abdominal muscles, but the strength of the diaphragm, as measured by the maximum transdiaphragmatic pressure, also declines with age.

Pulmonary function test changes are most affected by the age-related decreased compliance of the pulmonary system and decreased muscle strength. FEV1 and forced vital capacity (FVC) decline progressively with age. FEV1 decreases by 30 and 23 mL/yr in nonsmoking men and women, respectively, with an even greater decrease after 65 years. This is equivalent to an 8% to 10% decline in FEV1 each decade. The FVC in nonsmokers decreases 15 to 30 mL/year. The vital capacity progressively decreases,

SUMMARY

R E F E R E N C E S

SUMMARY

R E F E R E N C E S

Vital lu

lood f

Restin

diac i

Glomer

ular f

iltrati

d flow

Intimal hyperplasia

Superiorvenacava

Right atrium

Aortic valve

Tricuspid valve

Right ventricle

Inferior vena cava

Left atrium

Pulmonaryveins

Mitral valve

Leftventricle

Cardiac Structure

Vital lu

lood f

Restin

diac i

Glomer

ular f

iltrati

d flow

Intimal hyperplasia

Superiorvenacava

Right atrium

Aortic valve

Tricuspid valve

Right ventricle

Inferior vena cava

Left atrium

Pulmonaryveins

Mitral valve

Leftventricle

Cardiac Structure

Cardiac Function

Arterial Tree

RESPIRATORY SYSTEM

SUMMARY

R E F E R E N C E S

SUMMARY

R E F E R E N C E S

Vital lu

lood f

Restin

diac i

Glomer

ular f

iltrati

d flow

Intimal hyperplasia

Superiorvenacava

Right atrium

Aortic valve

Tricuspid valve

Right ventricle

Inferior vena cava

Left atrium

Pulmonaryveins

Mitral valve

Leftventricle

Cardiac Structure

Vital lu

lood f

Restin

diac i

Glomer

ular f

iltrati

d flow

Intimal hyperplasia

Superiorvenacava

Right atrium

Aortic valve

Tricuspid valve

Right ventricle

Inferior vena cava

Left atrium

Pulmonaryveins

Mitral valve

Leftventricle

Cardiac Structure

Cardiac Function

Arterial Tree

RESPIRATORY SYSTEM

SUMMARY

R E F E R E N C E S

SUMMARY

R E F E R E N C E S

Vital lu

lood f

Restin

diac i

Glomer

ular f

iltrati

d flow

Intimal hyperplasia

Superiorvenacava

Right atrium

Aortic valve

Tricuspid valve

Right ventricle

Inferior vena cava

Left atrium

Pulmonaryveins

Mitral valve

Leftventricle

Cardiac Structure

Vital lu

lood f

Restin

diac i

Glomer

ular f

iltrati

d flow

Intimal hyperplasia

Superiorvenacava

Right atrium

Aortic valve

Tricuspid valve

Right ventricle

Inferior vena cava

Left atrium

Pulmonaryveins

Mitral valve

Leftventricle

Cardiac Structure

Cardiac Function

Arterial Tree

RESPIRATORY SYSTEM

SUMMARY

R E F E R E N C E S

Vital lu

lood f

Restin

diac i

Glomer

ular f

iltrati

d flow

Intimal hyperplasia

Superiorvenacava

Right atrium

Aortic valve

Tricuspid valve

Right ventricle

Inferior vena cava

Left atrium

Pulmonaryveins

Mitral valve

Leftventricle

Cardiac Structure

Vital lu

lood f

Restin

diac i

Glomer

ular f

iltrati

d flow

Intimal hyperplasia

Superiorvenacava

Right atrium

Aortic valve

Tricuspid valve

Right ventricle

Inferior vena cava

Left atrium

Pulmonaryveins

Mitral valve

Leftventricle

Cardiac Structure

Cardiac Function

Arterial Tree

RESPIRATORY SYSTEM

and the residual volume gradually increases, leading to a relatively unchanged total lung capacity (vital capacity + residual volume). The functional residual capacity increases, although it is not as signifi cant because of the counteraction of the increased stiffness of the chest wall. The lungs’ diffusing capacity also decreases, mainly due to increased thickness of the alveolar basement membrane with advancing age, which leads to decreased gas-diffus-ing capabilities. The resulting ventilation-perfusion mis-match leads to higher alveolar-arterial oxygen gradients.

RENAL SYSTEM

There is a progressive decrease in the baseline kidney function after young adulthood. It remains uncertain whether these common changes refl ect subclinical disease or normal aging. In most individuals, between the ages of 30 and 85 years, there is a 20% to 25% loss of renal mass, most of which is cortex. The aging kidney also exhibits hyalinization of blood vessel walls and fewer glomeruli. This process progresses to hyalinizing arteriosclerosis and scattered arteriolar obliteration, with a resultant loss of nephrons secondary to ischemia. In addition, tubular senescence is frequent in the elderly. Histologically, tubular length decreases, interstitial fi brosis is seen, and tubular basement membrane constitution and anatomical features change with age. Tubular senescence blunts reab-sorption and secretion of solutes, leading to decreased capacity to reabsorb sodium and secrete potassium and hydrogen ions.

Functional changes parallel the anatomical changes. The kidneys show impaired concentrating capacity over time and a 10% decline in renal blood fl ow per decade after young adulthood. There is a sequential fall in the standardized glomerular fi ltration rate (GFR) with aging.9 Excluding individuals with inherent renal disease, there is a 50% to 63% decline in GFR from the ages of 30 to 80 years; in other words, GFR declines by about 1 mL/min per year. Serum creatinine levels often remain normal, despite signifi cantly reduced GFR, because of the con-comitant decreased production of creatinine in elderly persons (Fig. 203-3).

Elderly persons are limited in their ability to tolerate water deprivation and, contrarily, to tolerate water boluses. Decreased maximal urinary concentration is a partial explanation of nocturia in the elderly. Antidiuretic hormone (ADH) levels are not suppressed, so failure of ADH secretion cannot account for the age-associated urinary concentrating defect. Rather, a failure of normal renal responsiveness to ADH appears to mediate this change. It is unclear whether this failure results from a decreased medullary solute gradient or a decreased tubular response to ADH at the receptor.

The hormonal regulation of fl uid and electrolyte balance requires an intricate interaction among aldosterone, ADH, and atrial natriuretic peptide (ANP). Alterations in these hormones are partly responsible for changes in fl uid balance with aging. ANP is produced and secreted by the cardiac atria. The concentration of ANP is increased fi ve-fold over basal levels in the aged. The elderly exhibit an exaggerated increase in ANP in response to sodium chlo-ride infusions. The natriuretic response to exogenous ANP is exaggerated, as is the ability to suppress aldosterone.

Increased ANP levels presumably cause direct suppression of renin, with a secondary decrease in angiotensin II and in aldosterone, culminating in renal loss of sodium with aging. This may help protect against volume expansion. The secretion of aldosterone is also altered. Adaptation to salt and extracellular fl uid volume depletion is narrowed, with a blunted renin response to a low-sodium diet. This decreases angiotensin II and aldosterone response, with subsequent sodium loss. The clinical consequences are “salt wasting,” exemplifi ed by situations that paradoxically exaggerate clinical hypovolemia despite the body’s need for maximal sodium conservation (e.g., gastrointestinal losses). The direct aldosterone response to hyperkalemia is diminished, and tubular responsiveness to aldosterone appears to be less vigorous.

GASTROINTESTINAL AND HEPATOBILIARY SYSTEMS

In the elderly, the gastrointestinal and hepatobiliary systems are affected by changes in neuromuscular func-tion (primarily affecting the upper gastrointestinal tract), changes in the gastrointestinal tract structure (most notably in the distal colon), and changes in absorptive and secretory functions (predominantly in the small bowel and stomach, respectively).

Neuromuscular Function

Changes in the oropharynx and esophagus are primarily related to neuromuscular degeneration and changes in the ability to coordinate the complex refl exes required for successful swallowing and propulsion of food. Aberrant contraction can also be caused by muscle weakness. Failure to coordinate motility refl exes can cause numerous problems, including diffuse esophageal spasm, achalasia, and refl ux. Because these age-associated problems can also be caused by primary neurological conditions, it is important to differentiate neurological defi cits resulting

Reduced ability to absorb Na+

Reducednumber ofnephrons

Reducedglomerular

filtration rate

Decreasedcortical

thickness

FIGURE 203-3 Cross-section of the kidney, showing changes with advancing age.

FARMACOCINETICA� �

FARMACODINAMIA

Mayo Clin Proc, December 2003, Vol 78 Drug Therapy for the Elderly Patient 1573

Table 5. Factors Affecting Drug Disposition in Elderly Patients

Therapeutic andAge-related physiological change Pathologic condition environmental factor

AbsorptionIncreased gastric pH Achlorhydria AntacidsDecreased absorptive surface Diarrhea AnticholinergicsDecreased splanchnic blood flow Postgastrectomy CholestyramineDecreased gastrointestinal motility Malabsorption syndromes Drug interactions

Pancreatitis Food or mealsDistribution

Decreased cardiac output Congestive heart failure Drug interactionsDecreased total body water Dehydration Protein-bindingDecreased lean body mass Edema or ascites displacementDecreased serum albumin Hepatic failureIncreased α1-acid glycoprotein MalnutritionIncreased body fat Renal failure

MetabolismDecreased hepatic mass Cancer Dietary compositionDecreased hepatic blood flow Congestive heart failure Drug interactions

Fever InsecticidesHepatic insufficiency Tobacco (smoking)MalnutritionThyroid diseaseViral infection or

immunizationExcretion

Decreased renal blood flow Hypovolemia Drug interactionsDecreased glomerular filtration rate Renal insufficiencyDecreased tubular secretion

Adapted from Vestal and Dawson,76 with permission from Elsevier Science.

Even with careful medical care, elderly patients canexperience adverse drug effects. Sedative-hypnotics, anti-depressants, antianxiety drugs, and ethanol are less welltolerated by elderly patients, especially when multipleagents are used simultaneously. Disturbed mental functionand hallucinations may result from use of sympathomi-metic, antiparkinsonian, and/or anticholinergic drugs in theelderly population. In addition, these agents may exacer-bate glaucoma or urinary retention. Some apparent suicidesin elderly patients may be accidental deaths due to injudi-cious prescription of sedative drugs or repeated ingestionof prescribed drugs by a confused older patient.

Several pathophysiologic features of the aging processcontribute to adverse drug reactions in elderly patients.Moreover, anoxic, ischemic, diabetic, and hypothyroidstates increase sensitivity to morphine, barbiturates, andother sedative-hypnotic drugs.

In drug therapy for the elderly patient, it is important toindividualize therapy. Unexpected responses such as hy-persensitivity, tolerance, and toxicity must be anticipated.

Avoidance of Adverse Drug Reactions in the ElderlyPopulation.—Minimizing or avoiding adverse drug reac-tions in elderly persons is a rational goal on both personaland socioeconomic levels. Pharmacokinetic and pharmaco-dynamic limitations in elderly patients who frequently usemultiple drugs for several disease entities make them more

prone to adverse drug reactions. These reactions can occurat normal therapeutic drug doses and because of drug-druginteractions.

The following considerations in drug therapy for elderlypatients can help decrease adverse reactions.

1. Know what you are treating. Establishing a definitediagnosis often permits selection of the proper drug ordrugs and a treatment period. Treatment is aimed optimallyat changing the natural history of disease (diabetes, hyper-tension, major depression, coronary artery disease, rheu-matoid arthritis), although relief from the pain of arthriti-des, cancer, etc is an important therapeutic goal. The gainvs risk aspect of drug therapy for the elderly populationshould be considered in light of their greater propensity foradverse drug effects.

2. The elderly patient’s drug regimen should be re-viewed frequently. A physician should be alert to the possi-bility that other consulting physicians may be prescribing thesame or other drugs, creating the possibility of drug over-doses or drug-drug interactions. Also, patients may be usingover-the-counter drugs, including herbal remedies withproperties that influence prescribed drug therapy. Many phy-sicians ask patients to carry an updated card that lists theirprescribed and over-the-counter drugs (Table 576).

Elderly patients may have several conditions meritingdrug use. The simultaneous use of several drugs may result

Drug Therapy for the Elderly Patient Mayo Clin Proc, December 2003, Vol 781564

Symposium on Geriatrics

Drug therapy for older patients presents special prob-lems. Rather than provide a compendium of known

adverse reactions, we discuss the underlying reasons forthese reactions in elderly persons by reviewing the funda-mentals of pharmacology and suggesting ways to helppatients avoid adverse drug reactions.

During the past 5 decades, an increasing percentage ofthe population has attained geriatric status. Advances inmedical technology, surgical procedures, medical practice,and drug development have added to the length and qualityof life. The elderly population has a higher prevalence ofchronic and multiple diseases. Therefore, physicians oftenmust treat patients with multiple chronic diseases such ascardiovascular diseases, arthritis, diabetes, dementia, hy-pertension, and cancers. In the richest economies, medicaladvances have been accompanied by increased health carespending for the elderly population; these costs are increas-ing proportionally faster than the elderly segment of thepopulation. Drug therapy is used widely for all age groups,but in elderly persons, the risk is greater for an adverse drugreaction. The occurrence and effect of adverse drug reac-tions can be reduced by an increase in physician knowledgeand awareness of this problem.1-4

An adverse drug reaction is a noxious or unwantedresponse that occurs with a dose that usually would betherapeutic. If the response to a usual dose is excessive, it istermed idiosyncratic. If the observed signs and symptomsare an unexpected response of the immune system, the

Principles of Drug Therapy for the Elderly Patient

RUBIN BRESSLER, MD, AND JOSEPH J. BAHL, PHD

From the Department of Medicine, Sarver Heart Center, University ofArizona, Tucson, Ariz.

This work was supported by The Brach Foundation and the SarverHeart Center, University of Arizona, Tucson, Ariz.

Individual reprints of this article are not available. The entire Sympo-sium on Geriatrics will be available for purchase as a bound bookletfrom the Proceedings Editorial Office at a later date.

Physicians will treat larger numbers of elderly patients asthe US population ages. Being treated simultaneously formore than 1 condition with multiple prescription drugs isonly 1 reason why elderly patients are at greater risk ofexperiencing adverse drug reactions. The need for physi-cians to minimize the incidence of these reactions has be-come incumbent on both physicians and administrators.We review the underlying reasons why the elderly popula-tion is at risk of adverse drug reactions and summarize the

Css = concentration in the steady state; CYP = cytochromeP-450; VD = volume of distribution; (+) = dextro-enantiomer;(–) = levo-enantiomer

principles of drug-drug interaction, metabolism, and dis-tribution, which can help elderly patients receive properpharmacological treatment.

Mayo Clin Proc. 2003;78:1564-1577

response is termed hypersensitivity. A drug-drug interac-tion can occur when 2 or more drugs are used but usuallyhas no demonstrable adverse consequence. However, anotable portion of adverse drug reactions result from druginteractions in which the effects of one or more drugsbecome augmented or diminished beyond the limits of therequired therapeutic window.4-7

The increased frequency of adverse drug reactions hasbecome a focus of clinical pharmacology. The etiology ofunwanted drug effects has involved examination of drugpharmacokinetics (specifically, the time course of drugabsorption, distribution, metabolism, and excretion) andpharmacodynamics (especially the clinical aspects of al-tered physiological responses to drug action including di-minished compensatory homeostatic response in elderlypersons). Bleeding due to oral anticoagulants, hypoglyce-mia from diabetes treatment, and gastropathy associatedwith nonsteroidal anti-inflammatory drugs have been iden-tified in epidemiological studies as frequent adverse drugreactions in elderly persons.8,9 Because polypharmacy iscommon, the potential for adverse drug reactions has in-creased for every drug class.10-12

Adverse drug reactions in the elderly population areusually not idiosyncratic; they are more likely extensionsof the usual effects of the drug. Such reactions are respon-sible for both hospital admissions and prolonged hospitalstays. These adverse drug effects can be reduced and per-haps prevented by the physician anticipating the effects ofdrug toxicity and understanding how the patient’s age andhealth status will likely affect drug dosing.13

To understand how drug handling is altered for elderlypatients, we discuss the effects of aging on drug pharmaco-kinetics (absorption, distribution, and elimination). Nextwe consider issues of pharmacodynamic change that resultfrom altered sensitivity and modified response to a given

Mayo Clin Proc, December 2003, Vol 78 Drug Therapy for the Elderly Patient 1571

population. Decreases in the hepatic biotransformation ofdrugs with a high hepatic extraction ratio in elderly personsare predicted from the decrease in liver blood flow, al-though the large degree of individual variability in age-related and disease-related changes in organ functionmakes generalizations difficult. However, it is noteworthythat age-related decreases in hepatic biotransformation areassociated principally with the CYP monooxygenase sys-tem, whereas alternate metabolic pathways do not appearto be markedly affected by age. Clinical reports of de-creased oxidation of estrogens and benzodiazepines inwomen relative to men suggest that sex-dependent varia-tions in drug biotransformations also may be important inthe pharmacological and toxic responses to certain drugs.At this time, generalizations about such sex-specific differ-ences in drug metabolism are premature.8,28

Hepatic Disease.—Any impairment of normal liverfunction potentially will alter hepatic biotransformation. Adisproportionate number of elderly patients have liver dis-ease associated with excess alcohol use, gallstones, cholan-gitis, gallstone-induced pancreatitis, biliary cirrhosis, andfatty livers associated with diabetes or obesity. Adversedrug reactions may suggest liver dysfunction. The degreeto which CYP monooxygenase activity and hepatic elimi-nation are decreased is a function of the severity of liverdamage. A decreased hepatic biotransformation of tolbuta-mide, diazepam, and morphine in patients with hepaticdysfunction has been associated with exaggerated pharma-cological responses. Decreases in hepatic blood flow re-sulting from cardiac insufficiency or β-adrenergic block-ade also can affect the rate of hepatic biotransformation.The metabolism of drugs with a high hepatic extractionratio is limited by liver blood flow. For such drugs, adecreased hepatic blood flow results in decreased rates ofbiotransformation and clearance of the parent drug andtherefore a prolonged effect. Examples of drugs with highextraction ratios whose elimination likely is altered bychanges in liver blood flow are lidocaine, propranolol,verapamil, and amitriptyline.19,31,53

Renal Excretion of Drugs in the Elderly Popula-tion.—Renal blood flow decreases in elderly persons, evenin the absence of overt nephropathy. Renal blood flow isreduced by approximately 1% per year after age 50 years.55

Many drugs, active and inactive, are excreted by the kid-neys. A reduction of renal function can affect the elimina-tion of a drug if it is more than 60% excreted by thekidneys. Higher blood levels of drugs whose elimination isprimarily renal are found when the glomerular filtrationrate decreases. This may result in accumulation of drugsproducing higher drug levels for prolonged periods of time.Some drugs excreted primarily by the kidneys includeatenolol, sotalol, digoxin, lithium, amphotericin, pentami-

dine, procainamide, cimetidine, allopurinol, chlorprop-amide, and many antibiotics.

The assessment of renal function in elderly persons maynot be quantified accurately by the serum creatinine levelalone. Because creatinine formation is a function of musclemass, a normal serum creatinine level may be seen whenthe reduction in creatinine clearance or glomerular filtra-tion is substantial. Differences in creatinine clearance cor-relate with an approximate 2-fold increase in the half-life ofpenicillin in the elderly patient.56 Similarly, decreases indigoxin clearance occur in the elderly patient comparedwith the younger patient (mean ± SD clearance): 83±17mL/min per 1.73 m2 vs 53±9 mL/min per 1.73 m2.57

Consistent findings in the elderly population are a de-cline in renal function, decreased renal blood flow, de-creased renal mass, and decreased creatinine clearance(Table 4). Algorithms to estimate creatinine clearancebased on an individual’s age, sex, and serum creatininelevels can provide accurate estimates of the glomerularfiltration rate and have widespread clinical applicationswhen renal failure is not an issue. The effect of age can beshown by examining the most commonly used formula forestimating creatinine clearance:

Creatinine Clearance = (140 – Age [y]) × Lean Body Weight (kg)*

72 × Serum Creatinine (mg/dL)

*For female patients, multiply result of calculation by 0.85.58-60

When renal dysfunction is suspected, creatinine clearanceis more important than serum creatinine and the algo-rithm. For drugs excreted by the kidneys that have narrowtherapeutic indices, obtaining blood levels may be useful.Drugs such as digoxin, chlorpropamide, indomethacin,metformin, atenolol, methotrexate, procainamide, sali-cylic acid, and many antibiotics may require dosage ad-justments in elderly patients because of decreased renalfunction.

Phase II drug metabolism reactions, such as conjuga-tion, usually inactivate drugs. However, studies haveshown that a conjugated metabolite of morphine, mor-phine-6-glucuronide, is 40 times more potent than mor-phine.61 Approximately 80% of the analgesic action of theopiate derives from morphine-6-glucuronide after a singledose of morphine, and possibly even more at steady state.The use of morphine in patients with impaired renal func-tion results in prolonged effects and toxicity because of theaccumulation of morphine-6-glucuronide.62,63 The centralnervous system depressant effects of opiates, includingrespiratory depression, are especially dangerous in elderlypersons who are more sensitive to the drugs. Meperidine isoxidatively demethylated in the liver to the still-active nor-

Drug Therapy for the Elderly Patient Mayo Clin Proc, December 2003, Vol 781564

Symposium on Geriatrics

Drug therapy for older patients presents special prob-lems. Rather than provide a compendium of known

adverse reactions, we discuss the underlying reasons forthese reactions in elderly persons by reviewing the funda-mentals of pharmacology and suggesting ways to helppatients avoid adverse drug reactions.

During the past 5 decades, an increasing percentage ofthe population has attained geriatric status. Advances inmedical technology, surgical procedures, medical practice,and drug development have added to the length and qualityof life. The elderly population has a higher prevalence ofchronic and multiple diseases. Therefore, physicians oftenmust treat patients with multiple chronic diseases such ascardiovascular diseases, arthritis, diabetes, dementia, hy-pertension, and cancers. In the richest economies, medicaladvances have been accompanied by increased health carespending for the elderly population; these costs are increas-ing proportionally faster than the elderly segment of thepopulation. Drug therapy is used widely for all age groups,but in elderly persons, the risk is greater for an adverse drugreaction. The occurrence and effect of adverse drug reac-tions can be reduced by an increase in physician knowledgeand awareness of this problem.1-4

An adverse drug reaction is a noxious or unwantedresponse that occurs with a dose that usually would betherapeutic. If the response to a usual dose is excessive, it istermed idiosyncratic. If the observed signs and symptomsare an unexpected response of the immune system, the

Principles of Drug Therapy for the Elderly Patient

RUBIN BRESSLER, MD, AND JOSEPH J. BAHL, PHD

From the Department of Medicine, Sarver Heart Center, University ofArizona, Tucson, Ariz.

This work was supported by The Brach Foundation and the SarverHeart Center, University of Arizona, Tucson, Ariz.

Individual reprints of this article are not available. The entire Sympo-sium on Geriatrics will be available for purchase as a bound bookletfrom the Proceedings Editorial Office at a later date.

Physicians will treat larger numbers of elderly patients asthe US population ages. Being treated simultaneously formore than 1 condition with multiple prescription drugs isonly 1 reason why elderly patients are at greater risk ofexperiencing adverse drug reactions. The need for physi-cians to minimize the incidence of these reactions has be-come incumbent on both physicians and administrators.We review the underlying reasons why the elderly popula-tion is at risk of adverse drug reactions and summarize the

Css = concentration in the steady state; CYP = cytochromeP-450; VD = volume of distribution; (+) = dextro-enantiomer;(–) = levo-enantiomer

principles of drug-drug interaction, metabolism, and dis-tribution, which can help elderly patients receive properpharmacological treatment.

Mayo Clin Proc. 2003;78:1564-1577

response is termed hypersensitivity. A drug-drug interac-tion can occur when 2 or more drugs are used but usuallyhas no demonstrable adverse consequence. However, anotable portion of adverse drug reactions result from druginteractions in which the effects of one or more drugsbecome augmented or diminished beyond the limits of therequired therapeutic window.4-7

The increased frequency of adverse drug reactions hasbecome a focus of clinical pharmacology. The etiology ofunwanted drug effects has involved examination of drugpharmacokinetics (specifically, the time course of drugabsorption, distribution, metabolism, and excretion) andpharmacodynamics (especially the clinical aspects of al-tered physiological responses to drug action including di-minished compensatory homeostatic response in elderlypersons). Bleeding due to oral anticoagulants, hypoglyce-mia from diabetes treatment, and gastropathy associatedwith nonsteroidal anti-inflammatory drugs have been iden-tified in epidemiological studies as frequent adverse drugreactions in elderly persons.8,9 Because polypharmacy iscommon, the potential for adverse drug reactions has in-creased for every drug class.10-12

Adverse drug reactions in the elderly population areusually not idiosyncratic; they are more likely extensionsof the usual effects of the drug. Such reactions are respon-sible for both hospital admissions and prolonged hospitalstays. These adverse drug effects can be reduced and per-haps prevented by the physician anticipating the effects ofdrug toxicity and understanding how the patient’s age andhealth status will likely affect drug dosing.13

To understand how drug handling is altered for elderlypatients, we discuss the effects of aging on drug pharmaco-kinetics (absorption, distribution, and elimination). Nextwe consider issues of pharmacodynamic change that resultfrom altered sensitivity and modified response to a given

PRINCIPIOS DE

PRESCRIPCION

RACIONAL

Katzung B.G. (2012). Chapter 60. Special Aspects of Geriatric Pharmacology. In B.G. Katzung, S.B. Masters, A.J. Trevor (Eds), Basic & Clinical Pharmacology, 12e.

10/03/13 17:52AccessMedicine | Practical Aspects of Geriatric Pharmacology

de 2https://sibdi.ucr.ac.cr/http://www.accessmedicine.com/content.aspx?aID=55832401

proof" containers are often "elder-proof" if the patient has arthritis. Cataracts and macu-lar degeneration occur in a large number of patients over 70. Therefore, labels on pre-scription bottles should be large enough for the patient with diminished vision to reador should be color-coded if the patient can see but can no longer read.

Drug therapy has considerable potential for both helpful and harmful effects in the geri-atric patient. The balance may be tipped in the right direction by adherence to a fewprinciples:

1. Take a careful drug history. The disease to be treated may be drug-induced, ordrugs being taken may lead to interactions with drugs to be prescribed.

2. Prescribe only for a specific and rational indication. Do not prescribe omeprazolefor "dyspepsia." Expert guidelines are published regularly by national organiza-tions and websites such as www.UpToDate.com.

3. Define the goal of drug therapy. Then start with small doses and titrate to the re-sponse desired. Wait at least three half-lives (adjusted for age) before increasing thedose. If the expected response does not occur at the normal adult dosage, checkblood levels. If the expected response does not occur at the appropriate blood level,switch to a different drug.

4. Maintain a high index of suspicion regarding drug reactions and interactions.Know what other drugs the patient is taking, including over-the-counter andbotanical (herbal) drugs.

5. Simplify the regimen as much as possible. When multiple drugs are prescribed, tryto use drugs that can be taken at the same time of day. Whenever possible, reducethe number of drugs being taken.

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