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Geriatric Pharmacokinetics and the Kidney
Geriatric Pharmacokinetics and the Kidney William M. Bennett, MD • The general population Is aging and, as a result, drugs are Increasingly prescribed for a variety of medical conditions in a group of patients with multiple physiologic and pharmacokinetic abnormalities. The present report summarizes principles of prescribing for the elderly, especially those related to the decline In renal function that frequently occurs. © 1990 by the National Kidney Foundation, Inc. INDEX WORDS: Pharmacokinetics; geriatrics; renal insufficiency; aging.
ITH THE AGING of the general population, the proportion of Americans greater than 65 years of age continues to increase. Whereas in 1880, the percentage of the population over 65 was 2%, it is estimated that in the year 2030 that fraction will be up to 21%. At present, the elderly spend one quarter of this nation's 3.4 billion dollar annual drug expenditure. 1 The occurrence of adverse drug reactions in the elderly is increased compared with younger individuals, with a relative risk of two to three in patients in the eighth and ninth decades. 2 In a multicenter study of geriatric units, 15% of 2,000 consecutive admissions were complicated by adverse drug reactions, with more than half of those being the reason for admission. 3 When the medicine-taking habits of 800 British elderly were surveyed by Cartwright and Smith,4 they found 60% were taking prescription medications and 20% were on three or more drugs. Diuretics and other drugs for cardiovascular diseases were most prevalent. Interestingly, many patients remained compliant with their prescribed regimens without physician input, despite side effects that they attributed to the drug. 4 Duplications, contraindicated drugs and interacting drugs were common. 4
W
PHYSIOLOGIC CHANGES OF AGING THAT AFFECT GERIATRIC CLINICAL PHARMACOLOGY
There is little specific information available that can be generalized regarding drug absorption and distribution in the elderly. In patients with gastrointestinal pathology or previous surgery, drug absorption may be diminished. For example, antacids decrease the absorption of tetracycline, chlorpromazine, cimetidine, and isoniazid. The commonly prescribed anticholi-
nergic drugs may delay gastric emptying significantly.5 Hepatic first-pass metabolism and extraction of drugs may decline with age. Following a given oral dose of propranolol, an increased plasma concentration may be observed in elderly subjects.6 Likewise, drug distribution in the elderly may change depending on alterations in body fat composition and plasma protein concentrations. Obviously, important pharmacokinetic changes may occur due to nutritional problems. These are often difficult to distinguish from changes attributed to age alone. Renal excretion and hepatic metabolism of drugs are the main routes of drug elimination from the body. If either ofthese processes is altered, steady-state drug concentrations will increase, predisposing to adverse reactions. Between the fourth and eighth decades of life, the renal mass decreases by 20% due to interstitial fibrosis and vascular sclerosis. As glomeruli sclerose in the juxtamedullary cortex, blood flow to the medulla is maintained by anatomic connections between afferent and efferent arterioles. 7 Thus, renal blood flow per gram of renal cortex declines by approximately 10% per decade after age 30. 8 Glomerular filtration rate (GFR) also declines linearly with age beginning in the fourth decade .9 The rate of decline increases after the age of 60 to 17 mUmin/I.'?3 m2 per decade. 10 In many studies, GFR has been
From the Division of Nephrology and Hypertension, Department of Medicine, Oregon Health Sciences University, Portland, OR. Address reprint requests to William M. Bennett, MD, IA63, Division of Nephrology, Oregon Health Sciences University, Portland. OR 97201. © 1990 by the National Kidney Foundation. Inc. 0272-6386/90/1604-0003$3.00/0
American Journal of Kidney Diseases, Vol XVI, No 4 (October), 1990: pp 283-288
283
284
estimated by creatinine clearance. Since creatinine production and excretion may be reduced as muscle mass decreases, the serum creatinine value may not increase much as GFR decreases. In view of the recent emphasis on the role of protein intake as a determinant of GFR, it is possible that some decrement in GFR and renal blood flow previously ascribed to normal aging may be due to nutritional factors.l l Whether a lowered GFR due to poor protein intake has the same significance for drug accumulation as does reduction of renal function due to nephron dropout has not been studied. It is also possible that the decline in renal function with age is due to superimposed vascular disease with or without hypertension and not a necessary result of age per se. A longitudinal study from 1958 through 1981 followed 254 subjects without renal disease or risk factors. Overall, the decrease in renal function measured by creatinine clearance was 0.75 mLlmin/yr; however, one third of the subjects had no decline in renal function at all. 12 Thus, some aged individuals may have well-preserved renal function. For purposes of individual prescribing, it is best to base dosimetry on measurement of renal function and not on any presumption of senescent changes based on population studies. For example, renal diseases are known risk factors for acute renal insufficiency due to nonsteroidal antiinflammatory drugs. However, this increased risk of nephrotoxicity may be due to systemic vascular disease affecting the kidney and the frequent prescriptions for this class of drug in the elderly, rather than aging per se. \3 Drugs that are handled by glomerular filtration or tubular secretion often show diminished excretion that correlates with age-related declines in renal function. Aminoglycosides, amantadine, vancomycin, lithium, digoxin, procainamide, oral hypoglycemics, and cimetidine are examples of commonly prescribed drugs with reduced clearances and prolonged half-lives in the elderly requiring dosage adjustments to avoid toxicity. Hepatic metabolism of drugs by microsomal mixed-function oxidase enzymes may be reduced with increasing age. In addition, hepatic blood flow may decrease with age. Concomitant conditions such as congestive heart failure often further limit drug metabolism. For example,
WILLIAM M. BENNETI
many of the commonly prescribed benzodiazepines are metabolized to active metabolites, which depend on hepatic metabolism for elimination. Desmethyldiazepam, the active metabolite of both chlordiazepoxide and diazepam, has reduced clearance and prolonged elimination half-life in the elderly. 14 Certain benzodiazepines such as temazepam and lorazepam, which undergo conjugation reactions but not enzymatic conversion to active metabolites, are not influenced by age. Prolonged sedative effects from these latter congeners appears less likely. Interactions with drugs that decrease microsomal metabolism, such as cimetidine, may act synergistically with age-related changes to predispose to adverse drug reactions in the elderly. I The inability of the elderly to respond to altered physiological stimuli induced by drugs may lead to adverse consequences. This is particularly true in patients with renal disease. For example, patients with decreased GFR may not tolerate the sodium load (4.7 mEq/g) accompanying therapeutic doses of ticarcillin or the magnesium load that is a consequence of frequent dosing with magnesium-containing antacids or cathartics. Likewise, volume depletion induced by diuretics may produce serious compromise in organ perfusion due to impaired autoregulatory responses. The urinary sodium adaptation to volume depletion takes place slowly in elderly patients. 15 In addition, both basal and stimulated plasma renin activities decline with age, aggravating the hypotensive effects of volume depletion. The aldosterone homeostatic response to this stimulus is also limited. 16 Postural hypotension, which results in frequent adverse consequences such as stroke, falls, and bone fractures, may be exacerbated by impaired homeostatic adjustments to drug actions. Baroreceptor sensitivity declines in both normotensive and hypotensive elderly, as shown by Gribben et al.l7 Altered volume regulation, impaired vasomotor response, and increased venous compacitance also play important roles in the frequent postural changes seen with phenothiazines, diuretics, antihypertensives, and tricyclic antidepressants in the elderly. In practical terms, this information mandates a cautious approach to dose initiation and adjustments in the elderly.
285
GERIATRIC PHARMACOKINETICS
PHARMACOKINETIC ALTERATIONS IN RENAL INSUFFICIENCY DUE TO DISEASE AND/OR AGING
The elderly patient with renal dysfunction due to renal disease would appear to be in double jeopardy, inasmuch as the effects of renal disease are superimposed on those due to aging alone. It is unclear whether dosage adjustments and pharmacokinetics in patients with lower GFR due to poor protein intake or "healthy " aging are identical to patients with decreased GFR due to renal disease. Indeed , it has always been assumed impaired renal function in glomerular disease is equivalent to that induced by tubulointerstitial processes for purposes of dosage adjustment. This assumption has never been examined directly. In this report, it will be accepted that renal dysfunction in aging is the same as that due to pathological processes. Detailed discussion of specific drug dosage adjustments in renal failure and theoretical considerations are beyond the scope of this report and can be found in many standard sources. 18-20 Renal insufficiency may affect every organ system and aspect of body drug disposition. Thus , the presence of impaired renal function has a major impact on drug pharmacokinetics. Gastrointestinal drug absorption may be compromised by renal disease and the gastrointestinal symptoms of uremia may be exacerbated by drugs. 2 1 First-pass hepatic drug metabolism may be decreased with renal failure, resulting in increased amounts of active drug in the systemic circulation for any given oral dose. 19 This increased bioavailability mimics that seen with aging alone. 6 The increased bioavailability may also be obviated by decreased plasma protein binding, allowing more free (unbound) drug to be available for hepatic biotransformation. Altered drug-plasma protein binding in patients with renal insufficiency may have important effects on the volume of distribution, the quantity offree drug available for pharmacologic action , and the degree to which a drug can be eliminated by the liver or kidneys. Clinically relevant reduced binding is observed with acidic drugs such as phenytoin and salicylate. Failure to recognize decreased protein binding can result in serious toxicity if total drug concentrations are increased to achieve "therapeutic" levels . Renal insufficiency may alter hepatic metabo-
lism of drugs biotransformed by reduction or hydrolysis reactions . In addition, pharmacologically active metabolites may be dependent on adequate renal function for elimination. 22 Many adverse drug reactions in elderly patients with renal dysfunction may be due to the accumulation of active metabolites. 23 Renal drug excretion, which depends on glomerular filtration and tubular secretion, will be markedly altered in renal disease. Drug clearance will be reduced with prolongation of drug half-life. Unless dosage adjustments are made for drugs normally excreted by filtration and/or secretion, accumulation will occur with resultant toxic side effects. DRUG DOSIMETRY WITH RENAL INSUFFICIENCY
A rational approach to drug dosing in elderly patients, particularly those with renal impairment, requires a thorough history and physical examination. Particularly important is the history of previous drug allergy or toxicity, the use of concurrently prescribed or nonprescription medications, and the ingestion of alcohol or other recreational drugs. Physical assessment should include estimating the extracellular fluid volume, since the presence of edema, ascites, or dehydration may alter drug distribution and dose. Body weight and height need to be measured. For obese patients, the lean body weight should be calculated and drug doses should be estimated based on this derived parameter. Evidence of impaired excretory organ function should be sought. Stigmata of chronic liver disease are a clue that the dose of a drug requiring hepatic biotransformation may need to be severely altered. A specific diagnosis should be established before drug therapy is initiated. Elderly patients with renal dysfunction receive many concurrent medications, often without specific indications, so medication lists should be reviewed frequently. Many adverse drug effects could be avoided if fewer agents were used and potential drug interactions recognized. The first step to successful prescribing is to ascertain the current level of renal function. This is particularly important in elderly individuals who may have "normal" serum creatinine concentrations due to poor protein intake and
286
WILLIAM M. BENNETI
decreased muscle mass. The formula proposed by Cockroft and Gault is useful to estimate creatinine clearance from serum creatinine. 24
C"
(140 - Age) (Lean body weight [kg]) =
-------------------------
72 x serum creatinine (mg/dL)
The calculated value should be multiplied by 0.85 in women. This formula has been validated with measured creatinine clearances over a wide range of G FRs. 25 Lean body weight in men is approximated by 50 kg + 2.3 kg/in over 5 ft, and in women, 45.5 kg + 2.3 kg/in over 5 ft. When GFR is decreasing with acute disease, it is prudent to assume that the GFR is less than 10 mLimin to avoid overdosage. Drugs or their pharmacologically active metabolites that are normally excreted by the kidney require major dose adjustments in renal failure. These adjustments involve either interval extension between doses or dose size reduction. Loading doses are intended to generate a therapeutic steady-state drug level within a short period of time. Despite renal failure, the loading dose is usually not different from normal. Loading doses can be calculated if the volume of distribution and desired peak level are known. Since the volume of distribution is the amount of drug given divided by the plasma level, a desired loading dose can be calculated if the VD is known. If edema or ascites is present, a larger initial dose may be necessary. Conversely, dehydrated or debilitated individuals may require smaller initial doses. Maintenance doses are used to sustain a therapeutic level when administered subsequent to a loading dose. In the absence of a loading dose, maintenance doses will achieve 90% of their steady-state level in 3.3 half-lives. Maintenance doses may be modified in renal failure by the interval extension method, which calls for lengthening the time between doses, corresponding to the extent of delayed excretion or metabolism. This method is more practical for drugs with long half-lives. Alternately, the dosage reduction method simply reduces the amount of each dose, leaving the interval between doses the same as usual. This method sustains a more constant blood level. Blood, serum, and plasma drug concentrations may not be equivalent, usually depending
primarily on red blood cell compartmentalization (eg, cyclosporine). Drug levels can only be interpreted if the dosage schedule is known (amount, timing, and route of administration). A peak level is usually obtained I to 2 hours post-oral administration and 30 minutes postparenteral administration. It reflects the highest level achieved after the rapid distribution phase and before any substantial elimination has occurred. A trough level is obtained just before the next dose and better reflects the total body clearance of the drug. Drug levels are a valuable tool when used properly. This demands that the clinician know what level is desired. If the drug levels can be measured and if the volume of distribution and the therapeutic level desired are known, the amount of drug administered in any supplemental dose can be calculated. Subtract the present drug level from the desired drug level, giving the difference level. The supplemental dose is difference level x volume of distribution x body weight in kilograms. For loading doses, the desired level is the desired peak level; the present level is zero. The most frequent use of this formula is to supplement a dose using the trough level as the present level and the therapeutic level as the desired level. Pharmacokinetic information on commonly used drugs can be obtained from reference sources. 18-20 SPECIFIC SITUATIONS OF IMPORTANCE IN GERIATRIC PHARMACOLOGY FOR NEPHROLOGISTS
Hypertension
The treatment of hypertension in the elderly requires particular care and skill. Adverse reactions are frequent, since impaired homeostatic responses may add to diuretic-induced extracellular fluid volume depletion or postural hypotension. The Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure recommends that antihypertensive therapy in this age group should be initiated with smaller doses than usual, and that increases in dosage should be smaller and spaced at longer intervals. 26 Drugs that have postural hypotension as a frequent side effect should be used with caution in this age group. These include guanethidine, guanadrel, a-I-blockers, and labetolol. The report mentions calcium antagonists, ~-blockers, ACE inhibitors, and di-
287
GERIATRIC PHARMACOKINETICS
uretics as useful drugs for monotherapy in the elderly. Central and peripherally acting adrenergic inhibiting drugs should be reserved for treatment in patients with diastolic hypertension needing additional drugs for control. 26 The indications for treating isolated systolic hypertension in the elderly and recommended regimens for this difficult therapeutic problem await data from studies now in progress. Angina Pectoris and Congestive Heart Failure
Nitrate drugs are usually well tolerated in the elderly. Because cerebral hypoperfusion can be associated with arterial vasodilation , the elderly should be instructed to take sublingual nitrates for angina in the sitting or lying position. Beta-blockers and calcium antagonists, especially when used together, can exacerbate left ventricular dysfunction and conduction system abnormalities . Elderly patients may have diminished hepatic metabolism of calcium antagonists resulting in longer elimination half-lives. 27 In most patients, diuretic and peripheral vasodilators will provide good relief of symptoms and signs of congestive heart failure . The efficacy of chronic cardiac glycoside therapy in the absence of atrial fibrillation has been questioned in view of the high frequency of adverse reactions in elderly patients with reduced renal function. 28 Digoxin is mainly eliminated by glomerular filtration and maintenance doses can be as small as .0625 mg/d with impaired renal function. 29 However, some studies using low-dose digoxin therapy in elderly patients have shown improvement in cardiac function, even in the absence of atrial fibrillation . 30 In the elderly, toxic manifestations of cardiac glycosides may be qualitatively different than younger individuals. They also generally occur at lower drug concentrations. Central nervous system symptoms, including depression , delirium , psychosis, and confusion, are common symptoms of digitalis intoxication in the elderly. Since hypokalemia is a major predisposing factor to digitalis toxicity, elderly patients on maintenance digoxin need close monitoring of serum electrolytes. If quinidine and calcium antagonists are added to a regimen, digoxin levels may increase , requiring major downward digoxin dose adjustments. The total loading dose of digoxin is 8 to 12 j.Lg/kg in the elderly, administered in incremental doses. Mild to moderate renal insuf-
ficiency does not alter initial doses . In severe renal failure the volume of digoxin distribution is reduced and smaller loading doses are needed to avoid toxicity. Loop diuretics have increased volume of distribution and reduced total body clearance in the elderly.31 In addition, the rapidity ofthe therapeutic response may be slowed, although net electrolyte excretion over the first 6 hours is unchanged Y High doses of these potent drugs, particularly by the intravenous route , may produce ototoxicity. Concomitant use of salicylates, erythromycin, vancomycin, and aminoglycoside antibiotics can potentiate ototoxicity. With renal insufficiency, bumetanide is less ototoxic than furosemide. SUMMARY AND CONCLUSIONS
In the geriatric patient, decreased hepatic and renal drug clearances predispose to adverse drug reactions. Pharmacokinetic and pharmacodynamic changes of aging are additive to those produced by degenerative disease such as arteriosclerosis, hypertension, and nephrosclerosis . In addition, adverse drug reactions increase in direct proportion to the number of drugs taken. These considerations demand a conservative and rigorous approach to drug therapy in this rapidly expanding patient population. REFERENCES I. Nielson CP, Cusack BJ , Vestal RE: Geriatric clinical pharmacology and therapeutics , in Speight E (ed): Averys Drug Treatment (ed 3) . Auckland, NZ, ADlS , 1987, pp 160193 2. Hurwitz N: Predisposing factors in adverse reactions to drugs . Sr Med J 1 :5 36-539, 1969 3. Williamson J, Chopin JM: Adverse reactions to prescribed drugs in the elderly : A multicentre investigation. Age Ageing 9:73-80, 1980 4. Cartwright A, Smith C: Elderly People, Their Medications and Their Doctors. London, England , Routledge, 1988 5. Welling PG: Interactions affecting drug absorption. Clin Pharmacol 9:404-434, 1984 6. Castleden CM, George CF: The effects of aging on the hepatic clearance of propranolol. Sr J Clin Pharmacol 7:49-58 , 1979 7. Epstein M: Effects of aging on the kidney. Fed Proc 38: 168-172, 1979 8. Hollenberg NK, Adam s OF, Solomon HS: Senescence and the renal vasculature in normal man . Circ Res 34:309-316, 1974 9. Davies OF, Shock NW: Age changes in glomerular
288 filtration rate, effective renal plasma flow and tubular excretory capacity in adult males. J Clin Invest 29:496-507, 1950 10. Rowe Jw, Andres R, Tobin JD: The effect of age on creatinine clearance in men: cross-sectional and longitudinal study. J Gerontol31: 155-163, 1976 II. Lew S, Bosch J: personal communication, 1988 12. Lindeman RD, Tobin J, Shock NW: Longitudinal studies on the rate of decline in renal function with age. JAm Geriatr Soc 33:278-285, 1985 13. Blum RA, Watson WA: Aging and nonsteroidal antiinflammatory drug-induced renal dysfunction. Drug Intell Clin PharmacoI23:74-75, 1989 14. Greenblatt DJ, Allen MD, Harmatz JS, et al: Diazepam disposition determinants. Clin Pharmacol Thera 27: 301-310,1980 15. Epstein M, Hollenberg NK: Age as a determinant of renal sodium conservation in normal men. J Lab Clin Med 87:411-419,1976 16. Crane JG, Harris 11: Effect of aging on renin activity and aldosterone excretion. J Lab Clin Med 87:947-953, 1976 17. Gribben B, Pickering TG, Sleight P, et al: Effect of age and high blood pressure on baroreflex sensitivity in man. Circ Res 24:424-432, 1971 18. Golper TA, Bennett WM: Use of drugs in renal failure, in Massry S, Glossock R (eds.): Textbook of Nephrology. Baltimore, MD, Williams & Wilkins, 1989, pp 14461458 19. Bennett WM, AronoffGR, Golper TA, et al: Drug Prescribing in Renal Failure: Dosing Guidelines for Adults. Philadelphia, PA, American College of Physicians, 1987 20. Bennett WM: Guide to drug dosage in renal failure. Clin PharmacoI15:326-354, 1988
WILLIAM M. BENNETT
21. Craig R, Murphy T, Bigson TP: Kinetic analysis of o-Xylose absorption in normal subjects and in patients with chronic renal insufficiency. J Lab Clin Med 101:496-506, 1983 22. Reidenberg MM: The biotransformation of drugs in renal failure. Am J Med 62:482-485, 1977 23. Verbeeck RK, Branch RA, Wilkinson GR: Drug metabolites in renal failure: pharmacokinetic and clinical implications. Clin PharmacoI6:329-345, 1981 24. Cockroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 16:31-41, 1976 25. Parker RA, Bennett WM, Porter GA: Clinical estimation of creatinine clearance without urine collection. Dial Transplant 9:257-261,1980 26. The 1988 report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure. Arch Intern Med 148:1023-1038,1988 27. Freedman SB, Richman DR, Ashley 11: Verapamil kinetics in normal subjects and patients with coronary artery spasm. Clin Pharmacol Ther 30:644-652, 1981 28. Stults BM: Digoxin use in the elderly. J Am Geriatr Soc 30: 158-161, 1982 29. Donovan MD, Castleden CM, Pohl JEF: The effect of age on digitoxin pharmacokinetics. Br J Clin Pharmacol 11:401-409,1981 30. Ware JA, Luchi JM, Luchi RL: Effect of digoxin on ejection fraction in elderly patients with congestive heart failure. JAm Geriatr Soc 32:631-638, 1984 31. Kerremans AL, Tan Y, van Baars H, et al: Furosemide kinetics and dynamics in aged patients. Clin Pharmacol Ther 34: 181-189, 1983 32. Chaudry AY, Bing RF, Castleden CM, et al: The effect of aging on the response to fursemide in normal subjects. Eur J Clin PharmacoI27:303-311, 1984
ITH THE AGING of the general population, the proportion of Americans greater than 65 years of age continues to increase. Whereas in 1880, the percentage of the population over 65 was 2%, it is estimated that in the year 2030 that fraction will be up to 21%. At present, the elderly spend one quarter of this nation's 3.4 billion dollar annual drug expenditure. 1 The occurrence of adverse drug reactions in the elderly is increased compared with younger individuals, with a relative risk of two to three in patients in the eighth and ninth decades. 2 In a multicenter study of geriatric units, 15% of 2,000 consecutive admissions were complicated by adverse drug reactions, with more than half of those being the reason for admission. 3 When the medicine-taking habits of 800 British elderly were surveyed by Cartwright and Smith,4 they found 60% were taking prescription medications and 20% were on three or more drugs. Diuretics and other drugs for cardiovascular diseases were most prevalent. Interestingly, many patients remained compliant with their prescribed regimens without physician input, despite side effects that they attributed to the drug. 4 Duplications, contraindicated drugs and interacting drugs were common. 4
W
PHYSIOLOGIC CHANGES OF AGING THAT AFFECT GERIATRIC CLINICAL PHARMACOLOGY
There is little specific information available that can be generalized regarding drug absorption and distribution in the elderly. In patients with gastrointestinal pathology or previous surgery, drug absorption may be diminished. For example, antacids decrease the absorption of tetracycline, chlorpromazine, cimetidine, and isoniazid. The commonly prescribed anticholi-
nergic drugs may delay gastric emptying significantly.5 Hepatic first-pass metabolism and extraction of drugs may decline with age. Following a given oral dose of propranolol, an increased plasma concentration may be observed in elderly subjects.6 Likewise, drug distribution in the elderly may change depending on alterations in body fat composition and plasma protein concentrations. Obviously, important pharmacokinetic changes may occur due to nutritional problems. These are often difficult to distinguish from changes attributed to age alone. Renal excretion and hepatic metabolism of drugs are the main routes of drug elimination from the body. If either ofthese processes is altered, steady-state drug concentrations will increase, predisposing to adverse reactions. Between the fourth and eighth decades of life, the renal mass decreases by 20% due to interstitial fibrosis and vascular sclerosis. As glomeruli sclerose in the juxtamedullary cortex, blood flow to the medulla is maintained by anatomic connections between afferent and efferent arterioles. 7 Thus, renal blood flow per gram of renal cortex declines by approximately 10% per decade after age 30. 8 Glomerular filtration rate (GFR) also declines linearly with age beginning in the fourth decade .9 The rate of decline increases after the age of 60 to 17 mUmin/I.'?3 m2 per decade. 10 In many studies, GFR has been
From the Division of Nephrology and Hypertension, Department of Medicine, Oregon Health Sciences University, Portland, OR. Address reprint requests to William M. Bennett, MD, IA63, Division of Nephrology, Oregon Health Sciences University, Portland. OR 97201. © 1990 by the National Kidney Foundation. Inc. 0272-6386/90/1604-0003$3.00/0
American Journal of Kidney Diseases, Vol XVI, No 4 (October), 1990: pp 283-288
283
284
estimated by creatinine clearance. Since creatinine production and excretion may be reduced as muscle mass decreases, the serum creatinine value may not increase much as GFR decreases. In view of the recent emphasis on the role of protein intake as a determinant of GFR, it is possible that some decrement in GFR and renal blood flow previously ascribed to normal aging may be due to nutritional factors.l l Whether a lowered GFR due to poor protein intake has the same significance for drug accumulation as does reduction of renal function due to nephron dropout has not been studied. It is also possible that the decline in renal function with age is due to superimposed vascular disease with or without hypertension and not a necessary result of age per se. A longitudinal study from 1958 through 1981 followed 254 subjects without renal disease or risk factors. Overall, the decrease in renal function measured by creatinine clearance was 0.75 mLlmin/yr; however, one third of the subjects had no decline in renal function at all. 12 Thus, some aged individuals may have well-preserved renal function. For purposes of individual prescribing, it is best to base dosimetry on measurement of renal function and not on any presumption of senescent changes based on population studies. For example, renal diseases are known risk factors for acute renal insufficiency due to nonsteroidal antiinflammatory drugs. However, this increased risk of nephrotoxicity may be due to systemic vascular disease affecting the kidney and the frequent prescriptions for this class of drug in the elderly, rather than aging per se. \3 Drugs that are handled by glomerular filtration or tubular secretion often show diminished excretion that correlates with age-related declines in renal function. Aminoglycosides, amantadine, vancomycin, lithium, digoxin, procainamide, oral hypoglycemics, and cimetidine are examples of commonly prescribed drugs with reduced clearances and prolonged half-lives in the elderly requiring dosage adjustments to avoid toxicity. Hepatic metabolism of drugs by microsomal mixed-function oxidase enzymes may be reduced with increasing age. In addition, hepatic blood flow may decrease with age. Concomitant conditions such as congestive heart failure often further limit drug metabolism. For example,
WILLIAM M. BENNETI
many of the commonly prescribed benzodiazepines are metabolized to active metabolites, which depend on hepatic metabolism for elimination. Desmethyldiazepam, the active metabolite of both chlordiazepoxide and diazepam, has reduced clearance and prolonged elimination half-life in the elderly. 14 Certain benzodiazepines such as temazepam and lorazepam, which undergo conjugation reactions but not enzymatic conversion to active metabolites, are not influenced by age. Prolonged sedative effects from these latter congeners appears less likely. Interactions with drugs that decrease microsomal metabolism, such as cimetidine, may act synergistically with age-related changes to predispose to adverse drug reactions in the elderly. I The inability of the elderly to respond to altered physiological stimuli induced by drugs may lead to adverse consequences. This is particularly true in patients with renal disease. For example, patients with decreased GFR may not tolerate the sodium load (4.7 mEq/g) accompanying therapeutic doses of ticarcillin or the magnesium load that is a consequence of frequent dosing with magnesium-containing antacids or cathartics. Likewise, volume depletion induced by diuretics may produce serious compromise in organ perfusion due to impaired autoregulatory responses. The urinary sodium adaptation to volume depletion takes place slowly in elderly patients. 15 In addition, both basal and stimulated plasma renin activities decline with age, aggravating the hypotensive effects of volume depletion. The aldosterone homeostatic response to this stimulus is also limited. 16 Postural hypotension, which results in frequent adverse consequences such as stroke, falls, and bone fractures, may be exacerbated by impaired homeostatic adjustments to drug actions. Baroreceptor sensitivity declines in both normotensive and hypotensive elderly, as shown by Gribben et al.l7 Altered volume regulation, impaired vasomotor response, and increased venous compacitance also play important roles in the frequent postural changes seen with phenothiazines, diuretics, antihypertensives, and tricyclic antidepressants in the elderly. In practical terms, this information mandates a cautious approach to dose initiation and adjustments in the elderly.
285
GERIATRIC PHARMACOKINETICS
PHARMACOKINETIC ALTERATIONS IN RENAL INSUFFICIENCY DUE TO DISEASE AND/OR AGING
The elderly patient with renal dysfunction due to renal disease would appear to be in double jeopardy, inasmuch as the effects of renal disease are superimposed on those due to aging alone. It is unclear whether dosage adjustments and pharmacokinetics in patients with lower GFR due to poor protein intake or "healthy " aging are identical to patients with decreased GFR due to renal disease. Indeed , it has always been assumed impaired renal function in glomerular disease is equivalent to that induced by tubulointerstitial processes for purposes of dosage adjustment. This assumption has never been examined directly. In this report, it will be accepted that renal dysfunction in aging is the same as that due to pathological processes. Detailed discussion of specific drug dosage adjustments in renal failure and theoretical considerations are beyond the scope of this report and can be found in many standard sources. 18-20 Renal insufficiency may affect every organ system and aspect of body drug disposition. Thus , the presence of impaired renal function has a major impact on drug pharmacokinetics. Gastrointestinal drug absorption may be compromised by renal disease and the gastrointestinal symptoms of uremia may be exacerbated by drugs. 2 1 First-pass hepatic drug metabolism may be decreased with renal failure, resulting in increased amounts of active drug in the systemic circulation for any given oral dose. 19 This increased bioavailability mimics that seen with aging alone. 6 The increased bioavailability may also be obviated by decreased plasma protein binding, allowing more free (unbound) drug to be available for hepatic biotransformation. Altered drug-plasma protein binding in patients with renal insufficiency may have important effects on the volume of distribution, the quantity offree drug available for pharmacologic action , and the degree to which a drug can be eliminated by the liver or kidneys. Clinically relevant reduced binding is observed with acidic drugs such as phenytoin and salicylate. Failure to recognize decreased protein binding can result in serious toxicity if total drug concentrations are increased to achieve "therapeutic" levels . Renal insufficiency may alter hepatic metabo-
lism of drugs biotransformed by reduction or hydrolysis reactions . In addition, pharmacologically active metabolites may be dependent on adequate renal function for elimination. 22 Many adverse drug reactions in elderly patients with renal dysfunction may be due to the accumulation of active metabolites. 23 Renal drug excretion, which depends on glomerular filtration and tubular secretion, will be markedly altered in renal disease. Drug clearance will be reduced with prolongation of drug half-life. Unless dosage adjustments are made for drugs normally excreted by filtration and/or secretion, accumulation will occur with resultant toxic side effects. DRUG DOSIMETRY WITH RENAL INSUFFICIENCY
A rational approach to drug dosing in elderly patients, particularly those with renal impairment, requires a thorough history and physical examination. Particularly important is the history of previous drug allergy or toxicity, the use of concurrently prescribed or nonprescription medications, and the ingestion of alcohol or other recreational drugs. Physical assessment should include estimating the extracellular fluid volume, since the presence of edema, ascites, or dehydration may alter drug distribution and dose. Body weight and height need to be measured. For obese patients, the lean body weight should be calculated and drug doses should be estimated based on this derived parameter. Evidence of impaired excretory organ function should be sought. Stigmata of chronic liver disease are a clue that the dose of a drug requiring hepatic biotransformation may need to be severely altered. A specific diagnosis should be established before drug therapy is initiated. Elderly patients with renal dysfunction receive many concurrent medications, often without specific indications, so medication lists should be reviewed frequently. Many adverse drug effects could be avoided if fewer agents were used and potential drug interactions recognized. The first step to successful prescribing is to ascertain the current level of renal function. This is particularly important in elderly individuals who may have "normal" serum creatinine concentrations due to poor protein intake and
286
WILLIAM M. BENNETI
decreased muscle mass. The formula proposed by Cockroft and Gault is useful to estimate creatinine clearance from serum creatinine. 24
C"
(140 - Age) (Lean body weight [kg]) =
-------------------------
72 x serum creatinine (mg/dL)
The calculated value should be multiplied by 0.85 in women. This formula has been validated with measured creatinine clearances over a wide range of G FRs. 25 Lean body weight in men is approximated by 50 kg + 2.3 kg/in over 5 ft, and in women, 45.5 kg + 2.3 kg/in over 5 ft. When GFR is decreasing with acute disease, it is prudent to assume that the GFR is less than 10 mLimin to avoid overdosage. Drugs or their pharmacologically active metabolites that are normally excreted by the kidney require major dose adjustments in renal failure. These adjustments involve either interval extension between doses or dose size reduction. Loading doses are intended to generate a therapeutic steady-state drug level within a short period of time. Despite renal failure, the loading dose is usually not different from normal. Loading doses can be calculated if the volume of distribution and desired peak level are known. Since the volume of distribution is the amount of drug given divided by the plasma level, a desired loading dose can be calculated if the VD is known. If edema or ascites is present, a larger initial dose may be necessary. Conversely, dehydrated or debilitated individuals may require smaller initial doses. Maintenance doses are used to sustain a therapeutic level when administered subsequent to a loading dose. In the absence of a loading dose, maintenance doses will achieve 90% of their steady-state level in 3.3 half-lives. Maintenance doses may be modified in renal failure by the interval extension method, which calls for lengthening the time between doses, corresponding to the extent of delayed excretion or metabolism. This method is more practical for drugs with long half-lives. Alternately, the dosage reduction method simply reduces the amount of each dose, leaving the interval between doses the same as usual. This method sustains a more constant blood level. Blood, serum, and plasma drug concentrations may not be equivalent, usually depending
primarily on red blood cell compartmentalization (eg, cyclosporine). Drug levels can only be interpreted if the dosage schedule is known (amount, timing, and route of administration). A peak level is usually obtained I to 2 hours post-oral administration and 30 minutes postparenteral administration. It reflects the highest level achieved after the rapid distribution phase and before any substantial elimination has occurred. A trough level is obtained just before the next dose and better reflects the total body clearance of the drug. Drug levels are a valuable tool when used properly. This demands that the clinician know what level is desired. If the drug levels can be measured and if the volume of distribution and the therapeutic level desired are known, the amount of drug administered in any supplemental dose can be calculated. Subtract the present drug level from the desired drug level, giving the difference level. The supplemental dose is difference level x volume of distribution x body weight in kilograms. For loading doses, the desired level is the desired peak level; the present level is zero. The most frequent use of this formula is to supplement a dose using the trough level as the present level and the therapeutic level as the desired level. Pharmacokinetic information on commonly used drugs can be obtained from reference sources. 18-20 SPECIFIC SITUATIONS OF IMPORTANCE IN GERIATRIC PHARMACOLOGY FOR NEPHROLOGISTS
Hypertension
The treatment of hypertension in the elderly requires particular care and skill. Adverse reactions are frequent, since impaired homeostatic responses may add to diuretic-induced extracellular fluid volume depletion or postural hypotension. The Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure recommends that antihypertensive therapy in this age group should be initiated with smaller doses than usual, and that increases in dosage should be smaller and spaced at longer intervals. 26 Drugs that have postural hypotension as a frequent side effect should be used with caution in this age group. These include guanethidine, guanadrel, a-I-blockers, and labetolol. The report mentions calcium antagonists, ~-blockers, ACE inhibitors, and di-
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uretics as useful drugs for monotherapy in the elderly. Central and peripherally acting adrenergic inhibiting drugs should be reserved for treatment in patients with diastolic hypertension needing additional drugs for control. 26 The indications for treating isolated systolic hypertension in the elderly and recommended regimens for this difficult therapeutic problem await data from studies now in progress. Angina Pectoris and Congestive Heart Failure
Nitrate drugs are usually well tolerated in the elderly. Because cerebral hypoperfusion can be associated with arterial vasodilation , the elderly should be instructed to take sublingual nitrates for angina in the sitting or lying position. Beta-blockers and calcium antagonists, especially when used together, can exacerbate left ventricular dysfunction and conduction system abnormalities . Elderly patients may have diminished hepatic metabolism of calcium antagonists resulting in longer elimination half-lives. 27 In most patients, diuretic and peripheral vasodilators will provide good relief of symptoms and signs of congestive heart failure . The efficacy of chronic cardiac glycoside therapy in the absence of atrial fibrillation has been questioned in view of the high frequency of adverse reactions in elderly patients with reduced renal function. 28 Digoxin is mainly eliminated by glomerular filtration and maintenance doses can be as small as .0625 mg/d with impaired renal function. 29 However, some studies using low-dose digoxin therapy in elderly patients have shown improvement in cardiac function, even in the absence of atrial fibrillation . 30 In the elderly, toxic manifestations of cardiac glycosides may be qualitatively different than younger individuals. They also generally occur at lower drug concentrations. Central nervous system symptoms, including depression , delirium , psychosis, and confusion, are common symptoms of digitalis intoxication in the elderly. Since hypokalemia is a major predisposing factor to digitalis toxicity, elderly patients on maintenance digoxin need close monitoring of serum electrolytes. If quinidine and calcium antagonists are added to a regimen, digoxin levels may increase , requiring major downward digoxin dose adjustments. The total loading dose of digoxin is 8 to 12 j.Lg/kg in the elderly, administered in incremental doses. Mild to moderate renal insuf-
ficiency does not alter initial doses . In severe renal failure the volume of digoxin distribution is reduced and smaller loading doses are needed to avoid toxicity. Loop diuretics have increased volume of distribution and reduced total body clearance in the elderly.31 In addition, the rapidity ofthe therapeutic response may be slowed, although net electrolyte excretion over the first 6 hours is unchanged Y High doses of these potent drugs, particularly by the intravenous route , may produce ototoxicity. Concomitant use of salicylates, erythromycin, vancomycin, and aminoglycoside antibiotics can potentiate ototoxicity. With renal insufficiency, bumetanide is less ototoxic than furosemide. SUMMARY AND CONCLUSIONS
In the geriatric patient, decreased hepatic and renal drug clearances predispose to adverse drug reactions. Pharmacokinetic and pharmacodynamic changes of aging are additive to those produced by degenerative disease such as arteriosclerosis, hypertension, and nephrosclerosis . In addition, adverse drug reactions increase in direct proportion to the number of drugs taken. These considerations demand a conservative and rigorous approach to drug therapy in this rapidly expanding patient population. REFERENCES I. Nielson CP, Cusack BJ , Vestal RE: Geriatric clinical pharmacology and therapeutics , in Speight E (ed): Averys Drug Treatment (ed 3) . Auckland, NZ, ADlS , 1987, pp 160193 2. Hurwitz N: Predisposing factors in adverse reactions to drugs . Sr Med J 1 :5 36-539, 1969 3. Williamson J, Chopin JM: Adverse reactions to prescribed drugs in the elderly : A multicentre investigation. Age Ageing 9:73-80, 1980 4. Cartwright A, Smith C: Elderly People, Their Medications and Their Doctors. London, England , Routledge, 1988 5. Welling PG: Interactions affecting drug absorption. Clin Pharmacol 9:404-434, 1984 6. Castleden CM, George CF: The effects of aging on the hepatic clearance of propranolol. Sr J Clin Pharmacol 7:49-58 , 1979 7. Epstein M: Effects of aging on the kidney. Fed Proc 38: 168-172, 1979 8. Hollenberg NK, Adam s OF, Solomon HS: Senescence and the renal vasculature in normal man . Circ Res 34:309-316, 1974 9. Davies OF, Shock NW: Age changes in glomerular
288 filtration rate, effective renal plasma flow and tubular excretory capacity in adult males. J Clin Invest 29:496-507, 1950 10. Rowe Jw, Andres R, Tobin JD: The effect of age on creatinine clearance in men: cross-sectional and longitudinal study. J Gerontol31: 155-163, 1976 II. Lew S, Bosch J: personal communication, 1988 12. Lindeman RD, Tobin J, Shock NW: Longitudinal studies on the rate of decline in renal function with age. JAm Geriatr Soc 33:278-285, 1985 13. Blum RA, Watson WA: Aging and nonsteroidal antiinflammatory drug-induced renal dysfunction. Drug Intell Clin PharmacoI23:74-75, 1989 14. Greenblatt DJ, Allen MD, Harmatz JS, et al: Diazepam disposition determinants. Clin Pharmacol Thera 27: 301-310,1980 15. Epstein M, Hollenberg NK: Age as a determinant of renal sodium conservation in normal men. J Lab Clin Med 87:411-419,1976 16. Crane JG, Harris 11: Effect of aging on renin activity and aldosterone excretion. J Lab Clin Med 87:947-953, 1976 17. Gribben B, Pickering TG, Sleight P, et al: Effect of age and high blood pressure on baroreflex sensitivity in man. Circ Res 24:424-432, 1971 18. Golper TA, Bennett WM: Use of drugs in renal failure, in Massry S, Glossock R (eds.): Textbook of Nephrology. Baltimore, MD, Williams & Wilkins, 1989, pp 14461458 19. Bennett WM, AronoffGR, Golper TA, et al: Drug Prescribing in Renal Failure: Dosing Guidelines for Adults. Philadelphia, PA, American College of Physicians, 1987 20. Bennett WM: Guide to drug dosage in renal failure. Clin PharmacoI15:326-354, 1988
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21. Craig R, Murphy T, Bigson TP: Kinetic analysis of o-Xylose absorption in normal subjects and in patients with chronic renal insufficiency. J Lab Clin Med 101:496-506, 1983 22. Reidenberg MM: The biotransformation of drugs in renal failure. Am J Med 62:482-485, 1977 23. Verbeeck RK, Branch RA, Wilkinson GR: Drug metabolites in renal failure: pharmacokinetic and clinical implications. Clin PharmacoI6:329-345, 1981 24. Cockroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 16:31-41, 1976 25. Parker RA, Bennett WM, Porter GA: Clinical estimation of creatinine clearance without urine collection. Dial Transplant 9:257-261,1980 26. The 1988 report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure. Arch Intern Med 148:1023-1038,1988 27. Freedman SB, Richman DR, Ashley 11: Verapamil kinetics in normal subjects and patients with coronary artery spasm. Clin Pharmacol Ther 30:644-652, 1981 28. Stults BM: Digoxin use in the elderly. J Am Geriatr Soc 30: 158-161, 1982 29. Donovan MD, Castleden CM, Pohl JEF: The effect of age on digitoxin pharmacokinetics. Br J Clin Pharmacol 11:401-409,1981 30. Ware JA, Luchi JM, Luchi RL: Effect of digoxin on ejection fraction in elderly patients with congestive heart failure. JAm Geriatr Soc 32:631-638, 1984 31. Kerremans AL, Tan Y, van Baars H, et al: Furosemide kinetics and dynamics in aged patients. Clin Pharmacol Ther 34: 181-189, 1983 32. Chaudry AY, Bing RF, Castleden CM, et al: The effect of aging on the response to fursemide in normal subjects. Eur J Clin PharmacoI27:303-311, 1984