Acta Med Scand 1985; 218: 389-96

Antihypertensive, Haemodynamic and Metabolic Effects of Nifedipine Slow-Release Tablets in Elderly Patients

KNUD LANDMARK and JON DALE From the Department of Medicine, Lovisenberg Hospital, and Medical Department B, Rikshospitalet , Oslo, Norway

ABSTRACT. Landmark K, Dale J. (Department of Medicine, Lovisenberg Hospital, and Medical Department B, Rikshospitalet , Oslo, Norway .) Antihypertensive, haemodynamic and metabolic effects of nifedipine slow-release tablets in elderly patients. Acta Med Scand 1985; 218: 389-96.

In a double-blind, cross-over study for 8 weeks, including 10 non-hospitalized elderly hypertensives (average age 73.2 years), WHO stage 1-11, the antihypertensive effect of nifedipine slow-release tablets, 20 mg twice daily, was compared with placebo. Nifedipine reduced supine and standing blood pressure values significantly, and no signs of orthostatic hypotension were noted. An initial increment in heart rate was found after 1 week with a subsequent fall towards control values after 8 weeks of nifedipine administration. Heart rate pressure product in the supine position was reduced, and this reduction became statistically significant at the 8th week. Cardiac output measured non-invasively in 8 patients after 6-8 weeks’ nifedipine therapy, using an hex echocardiograph, was on an average 34% higher than in the placebo period (p<O.OS). Serum electrolytes, cholesterol, HDL cholesterol, blood glucose and renal function were not affected by the drug. Side- effects were few and mild. It is concluded that nifedipine is a potent antihypertensive agent which may represent an attractive first choice alternative in the treatment of elderly hypertensive patients. Key words: nifedipine, elderly hypertensives.

The calcium antagonistic drug, nifedipine, causes both coronary and peripheral vasodila- tion ( l ) , and its antihypertensive action has been well documented in several studies (2-6). Increased peripheral vascular resistance and a reduced cardiac output (Q) are the hall- marks of essential hypertension in the elderly (7). Nifedipine should therefore represent a logical approach to antihypertensive therapy in such patients. The clinical experience with nifedipine in elderly hypertensives is, however, limited (8). It was therefore of interest to study the effects of this drug in the aged. The present investigation was designed to evaluate the antihypertensive, haemodynamic, and metabolic effects of this agent in hypertensives older than 65 years. The study did not address itself to whether antihyper- tensive therapy was indicated or not.

PATIENTS AND METHODS Ten non-hospitalized patients (9 women and one man), average age 73.2 years (range 65-83), with hypertension (WHO stage 1-11), known for 1-20 years, participated in the study. One patient had angina pectoris, another well compensated congestive heart failure treated with digitoxin and furose- mide, the others had no signs of target organ damage. All patients were in sinus rhythm. Informed consent was obtained from all, and any prior antihypertensive medication was discontinued at least 2 weeks before entering the study.

After clinical and laboratory investigation, the patients who met the criterion of diastolic blood pressure 395 mmHg were included in the study. After a 2-week placebo run-in period they were randomized and allocated to a double-blind, cross-over trial including two 8-week periods during

Abbreviations: Q = cardiac output; HDL = high density lipoprotein, SAP = systolic blood pressure, DAP = diastolic blood pressure, MAP = mean arterial pressure, 2-D = two-dimensional.

390 K . Landmark and J . Dale Acta Med Scand 1985; 218

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which they received nifedipine (Adalat slow-release tablets), 20 mg twice daily, or placebo (Fig. 1). A double-dummy method w a s used.

Blood pressure and heart rate were measured after 5 min in the supine and after 2 min in the standing position, 2-3 hours after the morning dose of nifedipine. Results of the last 2 of 3 recordings were averaged and used. Blood pressure was measured by the same standard mercury sphygmomano- meter, diastolic values being taken at the disappearance of Korotkoff sounds (5th phase). Blood samples for determination of serum sodium (Na+), potassium (K+), calcium (Ca'+), creatinine, urea, cholesterol, high density lipoprotein (HDL) cholesterol and blood glucose were drawn in the mo.rning with the patients sitting and fasted.

Q was measured non-invasively, twice in 8 patients, after 6-8 weeks of nifedipine and placebo administration, using an hex echocardiograph. A two-dimensional (2-D) parasternal long-axis view of the heart guided M-mode registration of variations of left ventricular short diameter. Stroke volume was calculated using Teichholz formula (9), Q by multiplying by the heart rate.

The results are expressed as mean k SD. Student's t-test for paired comparison was used when observations in the control period were compared with those after nifedipine/placebo. Differences were regarded significant when pS0.05.

RESULTS

Nifedipine reduced significantly both supine and standing systolic (SAP), mean arterial (MAP), and diastolic blood pressures (DAP), the effects on systolic values being most pronounced. Thus, the pulse pressure amplitude decreased (Figs. 2 and 3). In the control period, all patients had supine blood pressure levels >160/95 mmHg. After 8 weeks of nifedipine therapy, 6 patients had pressure levels at or below this value. By the 8th week of drug therapy, the decrease in supine MAP was directly related to the pretreatment values (Fig. 4). No orthostatic reactions were reported. Mean heart rate, both in the supine and standing position, increased after one week of nifedipine treatment and fell thereafter towards control values (Fig. 5). The relationship between supine SAP and heart rate before and after nifedipine administration is shown in Fig. 6. Heart rate pressure product in the supine position was significantly reduced at the 8th week of nifedipine therapy (Fig. 7).

Left ventricular performance was significantly influenced by nifedipine administration as indicated by echocardiographic measurements (Table I). The difference between mean internal diastolic and systolic diameters increased @<0.05), as did Q, which was on an average 34% higher than in the placebo period (pC0.05). 2-D echocardiography demon- strated symmetric left ventricular contractions in all patients. The marked nifedipine-

Acta Med Scand 1985: 218 Nifedipine in elderly hypertensives 391

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Fig. 2. Supine systolic (SAP), mean arterial (MAP) , and diastolic blood pressure (DAP) in the control state (0 and I , 4 and 8 weeks after nifedipine (0) and placebo (0) administration. Values significantly different from C: * p<0.05, ** p<O.Ol, *** p<O.OOI.

Fig. 3. Standing systolic (SAP), mean arterial (MAP) , and diastolic blood pressure (DAP) in the control state (0 and I , 4 and 8 weeks after nifedipine (0) and placebo (0) administration. Values significantly different from C: * p<0.05, ** p<O.Ol, *** p<O.OOl.

induced decrease in MAP and the increase in Q show that the drug caused a pronounced fall in peripheral vascular resistance.

After 8 weeks of nifedipine therapy, serum concentrations of Na+, K', Ca", creatinine, urea, total cholesterol and HDL cholesterol were unaltered. The cholesterol ratio and blood glucose were also unchanged (Table 11).

Side-effects Moderate ankle oedema was observed in 4 patients while on nifedipine. One patient complained initially of moderate headache and palpitations. Three patients experienced

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392 K . Landmark and J . Dale Acta Med Scand 1985; 218

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Fig. 5. Heart rate in the supine and standing position in the control state (0 and 1, 4 and 8 weeks after nifedipine (0) and placebo (0) administration. Val- ues significantly different from C: * p<O.OS, :̂:: c 1 n 4 8 skkt c 1 rn 4 8 ** p<O.OI.

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moderate sensation of flushing 1-2 hours after ingestion of each dose. None of these complaints necessitated discontinuation of medication. No electrocardiographic disturb- ances were found.

DISCUSSION

The blood pressure lowering effect of nifedipine in elderly hypertensives was marked and more pronounced than that observed in younger hypertensives on the same dosage and after the same observation time (6). These findings are in accordance with a previous report (8). It is not known whether this phenomenon is due to enhanced sensitivity to and/or altered pharmacokinetics of the drug in the aged. Both in the supine and standing position, SAP declined more than DAP and orthostatic hypotension was not noted. The drug-induced decrease in supine MAP after 8 weeks of nifedipine therapy was closely related to pretreatment MAP values as previously found in younger hypertensives (6).

The effectiveness of baroreceptor activity is diminished by age and hypertension (10, 11). In spite of this, the nifedipine-induced reduction in both the supine and standing blood pressure values was associated with an initial increment in heart rate with a subsequent fall towards control values after 8 weeks of therapy. This observation indicates a gradual

1 1 0 1

Fig. 6. Relationship between supine systolic blood pressure (SAP) and heart rate in the control state (0 and 1 , 4 and 8 weeks (W) after nifedipine therapy. I I I I I I

150 160 170 180 190 200 SAP(rnrn Hgl

Acta Med Scand 1985: 21R Nifedipine in elderly hypertensives 393

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Weeks

resetting of baroreceptor activity, and is perhaps a beneficial response preventing ortho- static hypotension experienced by patients treated with other vasodilators (1 1, 12). Of importance in this connection is the fact that acute administration of nifedipine to hyper- tensives increased cerebral blood flow (13), and also that the drug does not seem to cause “venous pooling” (14).

In the elderly, essential hypertension is characterized by low Q states and high peripher- al vascular resistance (7). In our patients, 6-8 weeks of nifedipine administration signifi- cantly increased Q as estimated non-invasively, a method which has been shown to correlate with values obtained invasively (9), although measurement of left ventricular volumes from a single M-mode echocardiographic dimension is associated with several errors (15, 16). However, our patients served as their own controls, and 2-D echocardio- graphy demonstrated symmetrically contracting left ventricles in all. Therefore, the rela- tive changes recorded in Q, if not the absolute values, should be reliable in this study. Increases in Q after acute and chronic nifedipine administration have previously been described in younger patients (4, 17), and are related to reduced resistance to left ventricular emptying (14, 17, 18) and possibly also to improved abnormal diastolic function in hypertensive patients (19, 20, 21). The fall in heart rate pressure product, which is a major determinant of cardiac work (22), and the simultaneous increase in Q associated

Table I. Haemodynamic effects of 6 4 weeks of nifedipine ( N ) and placebo (P) administra- tion (mean _+ SD) LVDD = left ventricular internal diastolic diameter, LVSD = left ventricular internal systolic diameter, SV = stroke volume, Q = cardiac output

N P ~

LVDD (mm) 56.50k9.43 55.63+9.9n

SV (ml) 102.50+ 26.94 n1.75+ 19. I 1

LVSD (mm) 35.88f 10.1 I 38.50+ 11.35 LVDD-LVSD (mm) 20.63 f3.25* 17.13f3.48

Q (Vmin) 8.63 + 2.20* 6.4522.09

Significantly different from placebo: * p<0.05.

Acta Med Scand 198s: 218 394 K . Landmark and J . Dale

Table 11. Laboratory data before (C) and after 8 weeks of nifedipine ( N ) and placebo ( P ) (mean f SD) Figures in parentheses indicate no. of measurements if less than 10

C N C P

Serum Na+ (mmolh) 139.652.1 139.652.5 139.55 1.4 140.3f2.1 K+ (mmolfl) 4 .0f0.4 4.0f0.3 4.1 50.4 4.2f0.5 Ca++ (mmolh) (9) 2.44f0.10 2.45f0.12 2.44f0.10 2.43f0.10 Urea (mmolh) (9) 8.23f6.18 7.4652.17 7.8054.05 7.19f3.00 Creatinine (pmol/l) 100.5f30.3 105.9f26.1 100.6f32.1 103.5k25.9 Cholesterol (mmolh) (9) 6.38f I .40 6.24f 1.22 6.425 I . I6 6.345 1.28

HDL-cholesterol (mmolh) (9) 1.3550.35 1.36f0.36 1.32f0.33 1.30f0.37 Cholesterol ratio” 27.95 f9.48 27.49f5.62 26.23 56 . I4 26.2457.8 1 Blood glucose (mmolfl) 5.49f 1.47 5.76f 1.42 5.80f 2.04 5.56f0.75

HDL cholesterol x 100 LDL+ VLDL

with a fall in peripheral vascular resistance show that nifedipine has beneficial properties which tend to correct the above mentioned haemodynamic disturbances associated with hypertension in elderly patients.

Eight weeks of nifedipine therapy did not induce any noticeable biochemical changes. Thus, serum electrolytes, cholesterol, HDL cholesterol, cholesterol ratio, blood glucose and renal function remained unchanged. Diuretics are the most frequently recommended and used first-step drugs in the treatment of elderly hypertensives (23,24). However, these agents may cause hypovolaemia and postural hypotension ( 1 I , 25) and can initiate multiple metabolic side-effects which may offset their beneficial antihypertensive actions in the long run (26, 27). Elderly chlorothiazide-treated men with mild hypertension had a higher mortality rate due to a marked increase in the number of infarcts than patients not treated with this drug (28). Unfavourable influence of some ,!?-blockers on lipid metabolism has been described (29), and adverse reactions may also be associated with administration of these drugs to elderly patients (25, 30). There is also some evidence that responsiveness to B-blockade is reduced in the elderly (31,32). In contrast to nifedipine, ,&blockers reduce Q and increase peripheral vascular resistance, thereby intensifying the haemodynamic ab- normalities associated with hypertension and the ageing process (33).

In the present study, side-effects of nifedipine were few and without clinical importance. Central nervous system symptoms, which may be experienced in connection with other antihypertensive drugs such as methyldopa, clonidine, propranolol and metoprolol, did not appear (22).

Because of its unique and potent haemodynamic and antihypertensive actions, com- bined with a minimum of adverse reactions, good compliance to long-term treatment with nifedipine seems likely in elderly hypertensives. The drug therefore seems to be well suited for therapy of older patients.

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Received Jan. 2, 1985.

Correspondence: K. Landmark, MD, Department of Medicine, Lovisenberg Hospital, Lovisen- berggt. 17, N-0456 Oslo 4, Norway.