Experimental Gerontology, Vol. 25, pp. 375-381, 1990

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FACTORS INFLUENCING THE RESPONSES TO CALCIUM ANTAGONISTS IN ELDERLY PATIENTS WITH HYPERTENSION AND ISCHAEMIC HEART DISEASE

R. DONNELLYand H.L. ELLIOTT University Department of Materia Medica, Stobhill General Hospital, Glasgow G 2 1 3UW, United Kingdom

Abstract -- The results of a variety of studies that have investigated the effect of age on the pharmacokinetics and pharmacodynamics of calcium antagonist drugs have produced the following conclusions. Primarily, as a result of an age-dependent decline in plasma drug clearance, there is a tendency for elderly patients to have higher plasma drug concentrations than young patients. In terms of pharmacological response, there is good evidence of therapeutic efficacy in both hypertension and ischaemic heart disease, but there is no convincing evidence of any preferential age-related effect, particularly in relation to blood pressure reduction. Similarly and conversely, there is no convincing evidence that the elderly are at greater risk from the adverse effects of calcium antagonist drugs, particularly those which reflect the negative effects on cardiac conduction. An integrated mathematical method for describing antihypertensive response, which incorporates both pharmacokinetic and pharmacodynamic information, has been used to investigate the variability in antihypertensive effect with nifedipine and verapamil. There was no relationship between responsiveness (in mmHg/ng/mL) and patient age and plasma renin activity; however, responsiveness during chronic treatment was directly correlated with the height of the starting blood pressure and the response to the first dose. Key Words: calcium antagonists, angina, hypertension, elderly

INTRODUCTION CALCIUM ANTAGONISTdrugs are of established efficacy in the treatment of hypertension and ischaemic heart disease. Middle-aged and elderly patients are particularly likely to suffer from cardiovascular diseases and, since the proportion of individuals aged over 65 years is increasing in developed Western countries, it follows that many potential recipients of calcium antagonist drugs will fall into the " e l d e r l y " category. For this reason, it is important not only to establish that such drug treatment is safe and efficacious in the elderly population, but also to recognise

Correspondence to: R. Donnelly.

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R. DONNELLY and H.L. ELLIOT'f

that increasing age may lead to qualitative and quantitative changes in the pharmacokinefic and pharmacodynamic responses of these drugs. TREATMENT OF HYPERTENSION AND ISCHAEMIC HEART DISEASE IN THE ELDERLY Since angina pectoris is a symptomatic condition, there are perfectly clear grounds for administering drugs which provide symptomatic relief and the success of the calcium antagonists nifedipine, verapamil, and diltiazem, either alone or in combination with beta blockers, is well established. Although there are theoretical grounds for supposing that calcium antagonist drugs might have potential cytoprotective or coronary vasoditator properties relevant for acute myocardial ischaemia and myocardial infarction, there is, to date, no evidence that such potential has been fulfilled and no evidence of successful secondary prevention similar to that achieved with beta blocker drugs. In hypertension, the resuks of the EWPHE study (Amery et al., 1985) gave definitive evidence that treatment of hypertensive patients aged over 65 years led to a significant reduction, for example, in total cardiovascular mortality (-38%). This reduction in cardiovascular mortality was achieved with a drug regimen which now would be considered "old fashioned" but there are reasonable grounds for believing tha~ a similar beneficial effect might be achieved with currently preferred treatments. AGE AND DRUG DISPOSITION Advancing age is characterised by structural and physiological changes, which affect both drug disposition and pharmacological response. There is now increasing evidence, with various calcium antagonist drugs, that there are age-related differences in the achieved plasma concentrations and that this mainly reflects differences in absorption and clearance. For example, the maximum plasma concentrations after a single dose of nifedipine have been shown to be significantly increased with increasing age (Donnelly et al.. 1988), the plasma concentration-time profiles and the half-life of nifedipine were increased in the elderly (Robertson et al., 1988), the clearance of amlodipine (clearance/bioavailability) was significantly longer in a group of elderly subjects in comparison to a corresponding group of young subjects (Elliott et al.. 1988), and the disposition of verapamil was significantly different in elderly compared to young individuals (Abemethy et al., 1986). Whilst the weight of evidence suggests that elderly subjects tend to have reduced drug clearance and correspondingly increased plasma drug levels, not all studies have shown statistically significant age-related changes. Interindividual variability is often greatest in etdefly subjects, however, presumably as a reflection of genetic and environmental factors, concomitant diseases, etc. and this may be sufficient to obscure any differences attributable to increasing age itself. AGE AND PHARMACOLOGICAL RESPONSE The aging process results in a number of physiological changes which, potentially at least, may influence the response to drug treatment. These include changes in baroreflex activity (Gribben et al., 1971), reduction in cardiac output, decreased activity of the renin-angiotensin system, and changes in adrenergic responsiveness, particularly beta adrenoceptor responsiveness (Buhler and Bolli, 1985). Arising from these known physiological differences has come the

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concept that there may be a differential age-related response to different types of antihypertensive drugs and it has been reported that calcium antagonist drugs are particularly effective in elderly subjects whereas beta blockers are particularly effective in young subjects (Buhler et al., 1982). The data for the preferential age-related effects of calcium antagonists have come primarily from the work of Buhler and his colleagues, but few other studies have been able to confirm the constancy of this association. Furthermore, there is a contrary paper showing that the antihypertensive response to the dihydropyridine nitrendipine is least in the elderly age group (Ferrara et al., 1985). If the elderly were truly able to show an increased response to calcium antagonist drugs, then not only would this be reflected in advantageous therapeutic response, but it would also be reflected in an increased likelihood of undesirable or adverse effects. For this reas.on, several studies have addressed the problems of the cardiac effects of verapamil in the elderly. In a study of 14 patients with angina pectoris (Ahmed et al., 1989) assessments were made of LV ejection fraction and of cardiac conduction (electrocardiographic PR interval) following treatment with intravenous verapamil and following a 1-month treatment with oral verapamil 80 mg tid. There was no significant effect on LV ejection fraction, either at rest, or on supine exercise, and there was no significant effect on cardiac conduction in terms of PR prolongation. The principal conclusion of this study was that the elderly did not show an exaggerated response to verapamil in terms of the undesirable effects on cardiac function. Similarly, Abernethy et al. (1986) investigated cardiac conduction across an age range of 20-100 years and demonstrated that young subjects showed a much greater sensitivity to veraparnil with PR prolongations, which were four times greater than the elderly at their maximum. INTEGRATED PHARMACOKINETIC-PHARMACODYNAMIC ANALYSIS Many studies have investigated the variability in response to calcium antagonist drugs and produced a number of conflicting and often misleading statements, for example, about variations in responsiveness related to age (Buhler et al., 1982; Ferrara et al., 1985) and biochemical parameters, such as plasma renin activity (Buhler et al., 1982; Bidiville et al., 1988). Much of this confusion has arisen as a direct result of the inconsistent and often unsatisfactory methods used for describing antihypertensive response. For example, in most studies, response has been quantified on the basis of pharmacodynamics alone -- usually single measurements of blood pressure recorded on one or two separate occasions -- and no account has been taken of interindividual or time-related differences in plasma drug concentrations. Thus, the concept promulgated by Buhler and colleagues (1982), that calcium antagonists are significantly more effective in the elderly, cannot exclude the possibility of higher plasma drug concentrations in the elderly rather than increased responsiveness per se, since pharmacokinetic, as well as pharmacodynamic, variability accounts for interindividual differences in blood pressure response. It is perhaps not surprising that pharmacokinetic and pharmacodynamic variability with calcium antagonist drugs have been addressed separately because a clear relationship between plasma concentration and effect has not been established. It has been frequently suggested, not only with calcium antagonists, but also with many other antihypertensive drugs, that no predictable concentration-effect relationship exists. This probably reflects the negative findings of previous studies which typically have considered the response for groups of subjects rather than for individuals. There is now evidence for both nifedipine and verapamil that the fall in blood pressure can be related to the plasma drug concentration within an individual (Pasanisi

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R. DGNNELLYa~H,L. ELLIOTT

Plasma concentration

Effect

IiI Time Fro. 1. A diagrammatic representation of the temporal discrepancy between drug plasma concentration and effect which is characteristic of many types of drug.

and Reid, 1983; Meredith et al., 1987: Donnelly et al., 1988). This requires an integrated approach to pharmacodynamics and pharmacokinetics which has been variously called "concentration-effect analysis" or "pharmacodynamic modelling" (Holford and Sheiner, 1981). For many drugs, including the calcium antagonists, the relationship, within an individual, between plasma drug concentration and effect is not simple and direct. This often reflects the fact that the time course of the effect is out of phase with the time course of the plasma concentration profile, that is, delayed (Fig. 1). To take account of this phase discrepancy, Sheiner (1979) first proposed an extension to the basic pharmacokinetic model to incorporate an additional "'effect" compartment, and this became the basis for more sophisticated "concentration-effect analysis." The fundamental component of this approach is to relate the measured effect, for example, blood pressure reduction, to the drug concentration in the "effect" compartment (Ce). This concentration-effect relationship may be described by either a linear or nonlinear (sigmoid, Emax) model: E

=

mCe

+

Em~, C~

i --

E = Ce(50) + Ce

linear model sigmoid model

where E is the effect (i.e., the placebo-subtracted fall in blood pressure), C e, the drug concentration in the "effect" compartment, and i the intercept. The slope of this relationship, m, represents the "responsiveness" of an individual in terms of effect per unit drug concentration (mmHg/ng/ml). Theoretically, concentration-effect relationships should always conform to a n Emax equation, but in clinical studies most data points are obtained within a relatively restricted concentration-response range and, therefore, the simpler linear model is usually more appropriate. FACTORS DETERMINING THE RESPONSE TO CALCIUM ANTAGONISTS Individual patient responses to acute and chronic treatment with nifedipine and verapamil have recently been characterised using integrated kinetic-dynamic analysis (Donnelly et al.,

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379

TABLE 1. TWENTY EIGHT HYPERTENSIVEPAT1ENTS~FOLLOWINGA PLACEBORUN-IN PERIOD, RECEIVED 4---6 WEEKS TREATMENTWITH MFED1PIN~ (n = 14) OR VERAPA~CaL(n = 14) AS MONOrrIERAPY

Responsiveness (mean +- SD)-mmHg/ng/ml 1st Dose 4-6 Weeks Nifedipine Verapamil

-0.48 -0.13

- 0.20 --- 0 . 0 6

-0.49 -0.12

+ 0.17 - 0.06

Responsiveness (m) w a s calculated after the first dose a n d after 4 - 6 weeks treatment in terms o f the placebo-subtracted fall in systolic B P per unit drug concentration.

1988; Meredith et aI., 1987). The derived parameters from these studies are shown in Table 1. The measurements of responsiveness (m) derived from using a linear model incorporate both kinetic and dynamic data for individual patients and, in addition, take account of placebo effects and variations in blood pressure and drug concentration during the dosage interval. Having established an integrated mathematical description of antihypertensive response, which is comparable and reproducible, it is now feasible to start to address the more difficult but interesting task of identifying factors -- either demographic or biochemical -- which may contribute to the inter- and intrasubject variability in therapeutic effect. For the 28 patients who received nifedipine or verapamil the authors investigated the relationship between responsiveness (m) and possible determinants of response, such as age, pretreatment plasma renin activity (PRA), plasma noradrenaline, and starting blood pressure. These determinants have been comparatively assessed by means of multiple linear regression analysis. The R 2 values obtained from a 1-variable analysis, summarised in Table 2, represent the percentage variability in responsiveness which can be accounted for by each independent variable. For both drugs, age alone accounted for less than 10% of the interindividual variability in response to the first dose. In contrast, there were significant positive correlations between responsiveness and the height of the initial (pretreatment) blood pressure with R2 values of 37% and 65% for nifedipine and verapamil, respectively (Table 2). The relationship between starting blood pressure and the magnitude of the fall with treatment has been described previously with calcium antagonists (Erne et al., 1983). It has been suggested that the acute fall in blood pressure with a calcium antagonist is not a good predictor of the response obtained during long-term therapy (Bidiville et al., 1988). In TABLE 2. LINEAR REGRESSIONANALYSISTO INVESTIGATETHE INFLUENCE OF ACE, P R A , PLASMANORADRENALINE(NA) AND PRZrREATr~mNT BLOOD PRESStn~ ON THE VARIABILrrvIN RESPONSlVEmSSS(m) TO N1FEDIPINE AND VERAPAMILAMONGST28 HYPERTENSIVEPATIENTS

R2

Age PRA NA B l o o d pressure

Nifedipine (n = 14)

Verapamil (n = 14)

0.9% 4% 1% 37%

7% 9% 2% 65%

R 2 values for 1-variable a n a l y s i s .

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R, DONNELLYand H.L. ELLIOTT

controlled studies, however, using concentration-effect analysis, there were significant correlations for both nifedipine and verapamil between the responsiveness to the first dose and the responsiveness after 6 weeks ( r - 0 . 9 ) . Clearly, this may have potential application in c]inical practice as a means of quickly identifying poor or nonresponders and for determining individual dose requirements for optimum long-term blood pressure controt. There is some evidence of a relationship between the antihypertensive effect with dihydropyridine calcium antagonists and baseline sympathetic nervous activity (Ryman et al., 1987) and lymphocyte Na T and K-" levels (M'Buyamba-Kabangu, 1988), but these observations have not been confirmed. The majority of studies seem to suggest that in routine clinical practice biochemical measurements such as PRA are of negligible value for predicting individual patient responses. Demographic variables, however, warrant further investigation, and with the apparent failure of antihypertensive therapy to improve coronary heart disease mortality more information is needed about the interrelationship between antihypertensive drug response and other coronary risk factors, particularly cigarette smoking and hypercholesterolaerrda. For example, it is interesting that in both the MRC Trial (1985) and the IPPPSH Study (1985) ~ e fall in blood pressure with a beta blocker was less in cigarette smokers than nonsmokers, whereas no such difference occurred with bendrofluazide (MRC Trial. 1985). This variability in response amongst smokers either pharmacodynamic or pharmacokinetic -- has not been clearly explained and it remains to be seen whether similar differences occur with calcium antagonists.

CONCLUSIONS A number of studies have indicated that age has an important bearing on both the pharmacodynarnics and the pharmacokinetics of calcium antagonist drugs. Nevertheless. it is well established that calcium antagonists are safe and effective in the treatment of patients with ischaemic heart disease and hypertension, irrespective of age. Increasing age and the presumptive decline in hepatic function are associated with reduced drug clearance and a tendency for elderly subjects to have higher plasma drug concentrations but, since there is wide interindividual variability in the pharmacokinetic parameters, specific dosage reductions for elderly patients are not usually necessary. Both pharmacokinetic and pharmacodynamic variability with calcium antagonists contribute to interindividual differences in therapeutic response such that comparative clinically applicable assessments of therapeutic response are more appropriately undertaken by integrating the kinetic and dynamic information. Using such an approach it has been shown that the antihypertensive response to nifedipine and verapamil (per unit drug concentration) is not significantly different in elderly compared to young subjects.

REFERENCES ABERNETHY. D.R., SCHWARTZ, J.B., TODD, E.L., LUCHI, R.. and SNOW, E. Verapamil pharmacodynanucs and disposition in young and elderly hypertensive patients. Ann. Intern. Med. 5, 329-336, 1986. AHMED. J.A., ELLIOTT. H.L.. MEREDITH. P.A., and REID, J.L. Verapamil in middle-aged and elderly patients with angina pectoris: No evidence of increased susceptibility to the cardiac effects. Br. J, Clin. Pharmacol., in press, 1989. AMERY, A., BIRKENHAGER, W., BRIXKO, P., et al. Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly (EWPHE) Trial. Lancet |, 1349-1354, 1985.

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BIDIVILLE, J., NUSSBERGER, J., WAEBER, G., PORCHET, M., WAEBER, B., and BRUNNER, H.R. Individual responses to converting enzyme inhibitors and calcium antagonists. Hypertension 11, 166-173, 1988. BUHLER, F.R., HULTHEN, D.L., and KIOWSKI, W. The place of the calcium antagonist verapamil in antihypertensive therapy. J. Cardiovasc. Pharmacol. 4, 5350-5357, 1982. BUHLER, F.R. and BOLLI, P. Changes in cardiovascular responsiveness caused by age and high blood pressure: Implications for therapy. J. Cardiovasc. Pharmacol. 7, $206-$215, 1985. DONNELLY, R., ELLIOTT, H.L., MEREDITH, P.A., KELMAN, A.W., and REID, J.L. Nifedipine: Individual responses and concentration-effect relationships. Hypertension 12, 443-449, 1988. ELLIOTT, H.L., MEREDITH, P.A., REID, J.L., and FAULKNER, J.K. A comparison of the disposition of single oral doses of amlodipine in young and elderly subjects. J. Cardiovasc. Pharmacol. 12, $64-$66, 1988. ERNE, P., BOLLI, P., BERTEL, O., HULTHEN, U.L., KIOWSKI, W., MULLER, F., and BUHLER, F.R. Factors influencing the hypertensive effects of calcium antagonists. Hypertension 5, 97-102, 1983. FERRARA, L.A., FASANO, M.L., and SORO, S. Age-related antihypertensive effect of nitrendipine, a new calcium entry blocking agent. Eur. J. Clin. Pharmacol. 28, 473-474, 1985. GRIBBEN, P., PICKERING, T.G., SLEIGHT, P., and PETO, R. Effect of age and high blood pressure on baroreflex sensitivity in man. Circ. Res. 29, 424-431, 1971. HOLFORD, N.H.G. and SHEINER, L.B. Understanding the dose-effect relationship: Clinical application of pharmacokinetic-pharmacodynamic models. Clin. Pharmacokinet. 6, 429-453, 1981. IPPPSH Collaborative Group. The International Prospective Primary Prevention Study in Hypertension. J. Hypertens. 3, 379-392, 1985. M'BUYAMBA-KABANGU, J.R., LEPIRA, B., LIJNEN, P., TSHIANI, K., FAGARD, R., and AMERY, A. Intracellu~ar sodium and the response to nitrendipine or atenolol in African blacks. Hypertension 11, 100-105, 1988. MEREDITH, P.A., ELLIOTT, H.L., AHMED, J.A., and REID, J.L. Age and the antihypertensive efficacy of verapamil: An integrated pharmacokinetic-pharmacodynamic approach. J. Hypertens. 5(Suppl. 5), $219-$221, 1987. MRC Trial of treatment of mild hypertension: Principal results. Br. Med. J. 291, 97-104, 1985. PASANISI, F. and REID, J.L. Plasma nifedipine levels and fall in blood pressure in a 53 year old woman. Eur. J. Clin. Pharmacol. 25, 143-144, 1983. ROBERTSON, D.R.C., WALLER, D.G., RENWICK, A.G., and GEORGE, C.F. Age-related changes in the pharmacokinetics and pharmacodynamics of nifedipine. Br. J. Clin. Pharmacol. 25(3), 297-305. RYMAN, K.S., SPENCER, K.H., SHAKNOVICH, A., and CODY, R.J. Influence of baseline haemodynamic status and sympathetic activity on the response to nicardipine, a new dihydropyridine, in patients with hypertension or chronic congestive heart failure. Clin. Pharmacol. Ther. 41, 483-489, 1987. SHEINER, L.B., STARSKI, D.R., VOZEH, S., MILLER, R.D., and HAM, J. Simultaneous modelling of pharmacokinetics and dynamics: Application of d-tubocurarine. Clin. Pharmacol. Ther. 25, 358-371, 1979.

Factors influencing the responses to calcium antagonists in elderly patients with hypertension and ischaemic heart disease.

The results of a variety of studies that have investigated the effect of age on the pharmacokinetics and pharmacodynamics of calcium antagonist drugs ...
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