Disposition of Cardiovascular Drugs in the Elderly

Cardiovascular Pharmacotherapy III

0025--7125/89 $0.00

+

.20

Disposition of Cardiovascular Drugs in the Elderly

David J. Greenhlatt, MD*

Many individuals with cardiovascular disease are elderly, and old age has been associated with alterations in drug disposition and clinical drug effects. An understanding of the mechanisms and implications of altered cardiovascular drug response in elderly patients is of considerable importance for clinicians seeking to maximize the likelihood of therapeutic benefit from drug treatment, while minimizing the likelihood of toxicity.

MECHANISMS OF ALTERED DRUG RESPONSE IN THE ELDERLY Age-related changes in the response to cardiovascular drugs could be explained by either or both of two general mechanisms. The pharmacokinetic mechanism relates to age-dependent alterations in drug disposition and clearance. 16. 21. 34. 37 Even if the molecular receptor site mediating the effect of a specific drug is unaltered in old age, drug response, nevertheless, may change with age because of changes in drug distribution, elimination, and clearance. The second general mechanism relates to pharmacodynamic changes in the elderly. Based on this mechanism, the pharmacologic receptor that mediates drug effects acquires a different concentrationresponse relationship with age, so any given drug concentration at the *Professor of Psychiatry, Medicine, and Pharmacology, Tufts University School of Medicine; and Chief, Division of Clinical Pharmacology, Tufts-New England Medical Center, Boston, Massachusetts Supported in part by Grants MH-34223, AG-OOl06, and DA-05258 from the United States Public Health Service

Medical Clinics of North America-Vo!' 73, No. 2, March 1989

487

488

DAVID

J.

GREENBLATI

receptor elicits a different response (either increased or decreased) in the aging as opposed to the young organism. 25 . 40, 41 The most complex problems arise when both kinetic and dynamic factors simultaneously combine to influence drug response in the elderly. Interpreting Pharmacokinetic Changes in Old Age Clearance is the pharmacokinetic variable of primary importance in understanding age-related alterations in drug disposition. 14-16, 42 As in the case of clearance of an endogenous substance such as creatinine, clearance of exogenously administered drugs is expressed as units of volume divided by time. Although clearance is not an intuitively obvious concept, it best is pictured as the total amount of blood, serum, or plasma from which a substance is completely removed per unit of time. For most drugs, clearance is accomplished by a clearing organ, usually liver and/or kidney, in which case drug clearance cannot exceed blood flow to the clearing organ (hepatic and/or renal blood flow). The numerical value of clearance is the single best indicator of a given individual's capacity to remove or excrete a specific drug. For each drug, clearance is unique to each individual; for each individual, each drug has its own unique value of clearance. Thus, there is wide variability in clearance from drug to drug and from person to person. Although mean values are available in the literature, they usually are not directly useful for predicting clearance of a particular drug in a particular person. Following single doses of drugs, clearance is of importance because it determines, in part, the rate of drug elimination, based on the following relationship: elimination half-life

0.693 X Vd clearance

In this equation, Vd is the pharmacokinetic volume of distribution, expressed as units of volume (ml or L). Volume of distribution pharmacokinetically is independent of clearance, and is a physicochemically determined variable describing the extent of drug distribution throughout the body. For a certain group of drugs, clearance also may influence the peak serum or plasma concentration following single oral doses. This class of drugs includes those that are biotransformed by the liver, have values of hepatic clearance that approach hepatic blood flow, and, therefore, have important first-pass (presystemic) extraction after oral dosage. 3 , 29, 31 The extent of first-pass hepatic extraction is related to clearance after oral dosage. All else being equal, a lower value of clearance will lead to reduced first-pass extraction after oral dosage, and correspondingly greater systemic availability. \0 Reduced drug clearance in the elderly therefore may lead to prolonged elimination half-life after single doses. I, 3-5, 7, 10, 17-19, 28, 32, 35 For high-extraction drugs, reduced clearance also may cause increased peak serum or plasma concentrations after single oral doses. Clearance also assumes considerable importance during chronic dosage. The two principal determinants of the mean steady-state serum or plasma drug concentration (Css) during chronic dosage are the physician-deter-

DISPOSITION OF CARDIOVASCULAR DRUCS IN TIlE ELDERLY

489

mined rate of drug administration (dosing rate), and the biologically determined value of clearance. The relationship is as follows: Css

= dosing rate clearance

All else being equal, reduced clearance in the elderly implies increased values of Css, which, in turn, could increase the likelihood of drug toxicity. 13. 19,27 Knowledge of age-related changes in clearance may allow the dosing rate to be adjusted appropriately to keep Css in the desired range. Pharmacodynamic Changes in Old Age Intrinsic changes in drug sensitivity are difficult to quantitate in wellcontrolled studies. Methods must be developed for objective, reproducible measurement of pharmacodynamic response. Furthermore, dynamic changes must be isolated methodologically from pharmacokinetic changes. A number of well-controlled studes have investigated age-related alterations in cardiovascular "sensitivity," either to physiologic manipulations, or to administration of cardiovascular drugs. 4 , 5, 12, 24, 33, 35, 39, 43 No consistent summary statement can be applied to the data, however, because responses may be increased, decreased, or unchanged in the elderly, depending on the nature of the study population and the particular variable under consideration. The net clinical result may be complex and difficult to predict, because pharmacokinetic and pharmacodynamic changes may coexist. For the f3-blocker propranolop8 and the calcium antagonist verapamil,5 for example, pharmacokinetic studies indicate reduced drug clearance in the elderly, whereas pharmacodynamic assessments suggest reduced drug sensitivity. 5, 39 The net result of these offsetting changes for a given patient is uncertain. Propranolol in the Elderly An example of methodology for evaluating changes in cardiovascular kinetics in the elderly is illustrated in a study of 17 healthy volunteers aged 21 through 87 years, of whom nine were "young" (21 to 40 years) and eight were "elderly" (64 to 87 years). All subjects received a single lO-mg intravenous dose of propranolol hydrochloride. In two other trials, they received a single 40-mg oral dose of propranolol: once taken in the fasting state with water, and at another time taken 30 minutes after the start of a standard breakfast. Venous blood samples were drawn at multiple time points during 24 hours after each dose, and analyzed for intact propranolol concentrations by high-pressure liquid chromatographyll (Fig. 1). Standard pharmacokinetic methods were used to determine kinetic variables for intravenous and oral propranolol. 14,20 The eRect of age on the kinetics of intravenous propranolol was dependent on gender. In women, age had no significant effect on propranolol elimination half~life, volume of distribution, or clearance (Table 1, Fig. 2). Elderly, as opposed to young, men had prolonged propranolol half-life and reduced clearance (see Table 1, Fig. 2), however.

490

DAVID

80

i'. I .,

10 mg intravenous

E

..s 40 •

"I

Z

0

I~

0::

, 'I

i= c:(

w

•

0

zc:(

0::

a..

0

0::

a..

',l

'0

\\ \

\

\

0\ \

.'

10

FASTING

0

I~ ,I

0

.J

\

"

0

.J

\ \~

\0

I:,

20

0 Z

0

40mgoral

.~(t\

01

z

GREENBLATI

I \

.........

I-

J.

\

\

. \

\~\

r\,

•

POSTPRANDIAL \ \

, \

5

'\x

c:(

~

•

en

c:(

1

1>

.J

0\

a..

2

o 1

1

2

4

6

8

10

12

0

2

4

6

8

10

12

HOURS AFTER DOSE Figure 1. Plasma propranolol concentrations in a young male volunteer in each of' the three trials.

Overall systemic availability of oral propranolol in the fasting state averaged 0.29. Systemic availability was greater in men than in women regardless of age, and was not influenced by age as such. Age or sex did not influence peak plasma concentration or the time of peak concentration. Coadministration of propranolol with food reduced the peak plasma concentration relative to fasting dosage, but the difference was not significant. The time of peak concentration after postprandial dosage (2.6 hours) was significantly delayed, but systemic availability after postprandial administration essentially was identical to that measured in the fasting state. Experimental as well as human studies have indicated that propranolol clearance may be reduced importantly in the aging population. 8. 13. 23. 38 We observed that clearance of intravenous propranolol was reduced in elderly as opposed to young men, but age had no effect on propranolol clearance in women. Previous studies of a number of compounds biotransformed by microsomal oxidation also have indicated an age-related decrement in clearance that is more marked in men than in women. I. 16-19. 21 Because of its high hepatic clearance, systemic availability of oral propranolol in the administered doses averaged approximately 29 per cent, probably because of extensive first-pass extraction. Administration of oral propranolol 30 minutes after the start of a standard breakfast slowed the rate of absorption, but had no effect on absolute bioavailability. In prior studies, the effect of

491

DISPOSITlON OF CARDIOVASCULAR DRUGS IN THE ELDERLY

Table 1. Propranolol Kinetics in Relation to Age and Sex (± SE) VALUES FOR Young Elderly Female Male

Elderly Female

5 30.2 (±2.9) 76.8 (±3.5)

4 25.3 (±2.7) 55.6 (±5.0)

3 74.3 (± 1.4) 89.4 (±4.0)

5 70.2 (±4.2) 56.0 (±2.8)

3.7* (±0.7) 3.1 (±0.4) 10.8* (±2.3)

4.7 (± 1.0) 4.0 (± 1.0) 9.8 (±0.6)

5.8* (±0.3) 2.3 (±0.3) 4.6* (±0.7)

4.0 (±0.7) 3.0 (±0.4) 8.7 (±0.5)

60.1 (±14.3) 1.2 (±0.1) 3.3 (±0.4) 0.40 (±0.O6)

48.4 (±15.0) 1.8 (±0.5) 4.1 (± 1.3) 0.16 (±O.O3)

83.8 (±14.6) 2.0 (±0.5) 4.9 (± 1.1) 0.41 (±0.09)

37.7 (±7.2) 1.6 (±0.2) 3.4 (±0.5) 0.22 (±0.05)

46.9 (±6.6) 2.0 (±0.3) 3.4 (±0.6) 0.37 (±0.06)

33.2 (±6.5) 2.1 (±0.2) 4.8 (± 1.6) 0.20 (±0.03)

56.5 (±21.9) 2.3 (±0.2) 4.7 (±O.9) 0.34 (±0.12)

43.0 (±5.7) 1.9 (±0.2) 4.5 (± 1.0) 0.26 (±O.05)

Young Male Subjects Number Age (years) Weight (kg)

Intravenous Elimination half-life (hours) Volume of distribution (Llkg) Total clearance (mllminute/kg)

Fasting Oral Dosage Peak plasma concentration (ng/ml) Time of peak (hour after dose) Elimination half-life (hours) Systemic availability (fraction of IV)

Postprandial Oral Dosage Peak plasma concentration (ng/ml) Time of peak (hour after dose) Elimination half-life (hours) Systemic availability (fraction of IV)

~1EAN

*Significant difference (P < 0.(5) between young and elderly of the same sex, based on Student's one-tailed Hest

food on propranolol absorption has been highly variable, 6. 20. 36 probably because of differences in composition of meals, the time of dosing relative to when food was administered, and unexplained individual variation.

COMPLICATING FACTORS IN PHARMACOGERIATRIC STUDIES Age is but one variable that can influence drug kinetics and dynamics. Drug disposition or response may be influenced equally strongly by factors such as cigarette smoking, gender, body habitus, coexistence of disease states, or coadministration of other medications. 2 , 13, 15, 16, 21, 38 Many cardiovascular drugs are bound to plasma protein, predominantly albumin or a-I acid glycoprotein, Age- or disease-related changes in the concentration of these two binding proteins may alter the extent of protein binding. Although changes in binding have no influence on a drug's clinical effects, reciprocal alterations in total (free plus bound) drug concentration will

492 _

.,.

DAVID

E

GREENBLATI

20

•

~

"c 'E "-

J.

18 16

ILl

u Z 14 et 0: et ILl 12 ..../ u ..../

0

..../

0 Z

et 0:

a.

0 0:

a.

• 0

10 8

0 Z

o

o

•

6

IJl ::;)

Figure 2. Relation of age to clearance of intravenous propranolol in men (r = -0.67, 0.05 < P < 0.1) and in women (r = -0.48, NS).

0

4

ILl

> et

0: I-

~

2 0

20

30

40

50

60

AGE (years)

70

80

90

occur, which, in turn, will influence the interpretation of pharmacokinetic results. 20 A number of drugs undergo stereoselective clearance,30 and the stereoisomers themselves may undergo selective age-related changes in clearance. 9 Research aimed at elucidating changes in drug disposition and response that are attributable to age as such must include methodology that either controls for, or at least identifies, these possible confounding factors. ACKNOWLEDGMENTS We are grateful for the assistance of Darrell R. Abernethy, Marcia K. Divoll, Hermann

R. Ochs, Jerold S. Harmatz, and Richard I. Shader.

REFERENCES 1. Abernethy DR, Greenblatt DJ: Impairment oflidocaine clearance in elderly male subjects. J Cardiovasc Pharmacol 5:1093-1096, 1983 2. Abernethy DR, Greenblatt DJ: Lidocaine disposition in obesity. Am J Cardiol 53:11831186, 1984 3. Abernethy DR, Greenblatt DJ, Shader RI: Imipramine and desipramine disposition in the elderly. J Pharmacol Exp Ther 232:183-188, 1985 4. Abernethy DR, Schwartz JB, Plachetka JR, et al: Comparison in young and elderly patients of pharmacodynamics and disposition of labetalol in systemic hypertension. Am J Cardiol 60:697-702, 1987 5. Abernethy DR, Schwartz JB, Todd EL, et al: Verapamil pharmacodynamics and disposition in young and elderly hypertensive patients. Ann Intern Med 105:329-336, 1986 6. Bai SA, Walle UK, Walle T: Influence of food on the intravenous and oral dose kinetics of propranolol in the dog. J Pharmacokin Biopharmaceut 13:229-241, 1985 7. Bowdle TA, Freund PR, Slattery JT: Age-dependent lidocaine pharmacokinetics during

DISPOSITION OF CARDIOVASCULAR DRUCS 1;\1 TilE ELDEHLY

8. 9. 10, lL 12. 13. 14. 15, 16, 17, 18, 19, 20, 2L 22. 23, 24. 25, 26, 27. 28, 29, 30, 3L 32. 33. 34.

493

lumbar peridural anesthesia with lidocaine hydrocarbon ate or lidocaine hvdrochloride Reg Anesthes 11:123-127, 1986 " Castleden CM, George CF: The effect of aging on the hepatic clearance of propranolol. Br J Clin Pharmacol 7:49-54, 1979 Chandler MHH, Scott SR, Blouin RA: Age-associated stereoselective alterations in hexobarbital metabolism, Clin Pharmacol Ther 43:436-441, 1988 Cusack B, O'Malley K, Lavan J, et al: Protein binding and disposition of lignocaine in the elderly. Eur J Clin Pharmacol 29:323-329, 1985 Divoll M, Greenblatt DJ, Arendt RM: Propranolol kinetics: Use of automated liquid chromatography. Int J Clin Pharmacol 22:457-460, 1984 Eichler H-G, Hiremath A, Katzir 0, et al: Absence of age-related changes in venous responsiveness to nitroglycerin in vivo in humans. Clin Pharmacol Ther 42:521-524, 1987 Feely J, Crooks J, Stevenson IH: The influence of age, smoking, and hyperthyroidism on plasma propranolol steady-state concentration. Br J Clin Pharmacol 12:73-78, 1981 Greenblatt DJ, Koch-Weser J: Clinical pharmacokinetics. N Engl J Med 293:702-705, 964-970, 1975 Greenblatt DJ, Shader RI: Pharmacokinetics in Clinical Practice. Philadelphia, WB Saunders, 1985 Greenblatt DJ, Abernethy OR, Shader RI: Pharmacokinetic aspects of drug therapy in the elderly. Ther Drug Monit 8:249-255, 1986 Greenblatt DJ, Divoll M, Abernethy OR, et al: Antipyrine kinetics in the elderly: Prediction of age-related changes in benzodiazepine oxidizing capacity, J Pharmacol Exp Ther 220:120-126, 1982 Greenblatt DJ, Divoll M, Abernethy OR, et al: Alprazolam kinetics in the elderly: Relation to antipyrine disposition. Arch Gen Psychiatry 40:287-290, 1983 Greenblatt DJ, Divoll M, Puri SK, et al: Reduced single-dose clearance of clobazam in elderly men predicts increased multiple-dose accumulation. Clin Pharmacokinet 8:8394, 1983 Greenblatt DJ, Sellers EM, Koch-Weser J: Importance of protein binding for the interpretation of serum or plasma drug concentrations. J Clin Pharmacol 22:259-263, 1982 Greenblatt DJ, Sellers EM, Shader RI: Drug disposition in old age. N Engl J Med 306:1081-1088, 1982 Harmatz JS, Greenblatt DJ: A SIMPLEX procedure for fitting nonlinear pharmacokinetic models. Comp BioI Med 17:199-208, 1987 Iwamoto K, Watanabe J, Araki K, et al: Effect of age on the hepatic clearance of propranolol in rats, J Ph arm Pharmacol 37:466-470, 1985 Kaijser L, Sachs C: Autonomic cardiovascular responses in old age. Clin Physiol 5:347357, 1985 Katano Y, Kennedy RH, Stemmer PM, et al: Aging and digitalis sensitivity of cardiac muscle in rats. Eur J Pharmacol 113:167-178, 1985 Melander A, McLean A: Influence of food intake on presystemic clearance of drugs. Clin Pharmacokinet 8:286-296, 1983 Nation RL, Triggs EJ, Selig M: Lignocaine kinetics in cardiac patients and aged subjects. Br J Clin Pharmacol 4:439-448, 1977 Ochs HR, Greenblatt DJ, Woo E, et al: Reduced quinidine clearance in elderly persons. Am J Cardiol 42:481-485, 1978 Ochs HR, Grube E, Greenblatt DJ, et al: Kinetics and cardiac effects of propranolol in humans. Klin Wochenschr 60:521-525, 1982 Ochs HR, Hajdu P, Greenblatt DJ: Pharmacokinetics and dynamics of penbutolol in humans: Evidence for pathway-specific stereoselective clearance. Klin \Vochenschr 64:636-641, 1986 Pond SM, Tozer TN: First-pass elimination: Basic concepts and clinical consequences. Clin Pharmacokinet 9:1-25, 1984 Roux A, Henry JF, Fouache Y, et al: A pharmacokinetic study of acebutolol in aged subjects as compared to young subjects. Gerontology 29:202-208, 1983 Sachs C, Hamberger B, Kaijser L: Cardiovascular responses and plasma catecholamines in old age. Clin Physiology 5:553-565, 1985 Schmucker DL: Aging and drug disposition: An update. Pharmacol Rev 37:133-148, 1985

494

DAVID

J.

GREENBLATI

3S. Schwartz JB, Abernethy DR: Responses to intravenous and oral diltiazem in elderly and younger patients with systemic hypertension. Am J CardioIS9:1111-1117, 1987 36. Svensson CK, Edwards DJ, Mauriello PM, et al: Effect of food on hepatic blood flow: Implications in the "food effect" phenomenon. Clin Pharmacol Ther 34:316-323, 1983 37. Vestal RE: Pharmacology and aging. JAm Ceriatr Soc 30:191-200, 1982 38. Vestal RE, Wood AJJ, Branch RA, et al: Effects of age and cigarette smoking on propranolol disposition. Clin Pharmacol Ther 26:8-1S, 1979 39. Vestal RE, Wood AJJ, Shand DC: Reduced f3-adrenoceptor sensitivity in the elderly. Clin Pharmacol Ther 26:181-186, 1979 40. Wellstein A, Palm D: Correlation between pharmacological response, kinetics of plasma concentration and in vitro receptor affinities exemplified with f3-adrenoceptor blocking drugs. Methods Find Exp Clin Pharmacol 6:641-644, 1984 41. Wellstein A, Palm D, Belz CC, et al: Receptor binding characteristics and pharmacokinetic properties as a tool for the prediction of clinical effects of f3-blockers. Arzneim Forsch 3S:2-6, 1985 42. Wilkinson CR: Clearance approaches in pharmacology. Pharmacol Rev 39:1-47, 1987 43. Wood M, Hyman S, Wood AJJ: A clinical study of sensitivity to sodium nitroprusside during controlled hypotensive anesthesia in young and elderly patients. Anesth Analg 66:132-136, 1987 Division of Clinical Pharmacology Tufts-New England Medical Center Box 1007 171 Harrison Avenue Boston, MA 02111