LABETALOL IN SEVERE AND RESISTANT HYPERTENSION

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1 Br. J. clin. Pharmac. (1979), 8, 13S-17S LABETALOL IN SEVERE AND RESISTANT HYPERTENSION King's College Hospital Renal Unit, Dulwich Hospital, London SE22 8PT, UK 1 The efficacy of labetalol in the treatment of severe hypertension (diastolic > 115 mm Hg) was studied retrospectively. Ten patients were followed for more than 6 months. At 6 months, eight were well controlled and the mean dose in those was 975 mg daily. Four of these were receiving labetalol alone; two were on labetalol and diuretic only. 2 Three patients were resistant to doses to 1600, 1800 and mg daily respectively; two of these were controlled with increased doses of vasodilator drugs. In two cases labetalol had produced large falls in the standing BP while not influencing the supine BP. 3 Three other resistant patients were seen, of whom one merely required an increase in dose to 2200 mg daily and the addition of a diuretic. Both the others were elderly, had severe vascular disease, and suffered disabling postural hypotension on a dose of labetalol which did not influence the supine BP. Labetalol can control severe hypertension. There remain patients whose supine BP is not influenced by a dose of labetalol which produces marked postural hypotension. Introduction FORTY-NINE patients have entered a study of the use of labetalol in hypertension at this unit. We aimed to assess the efficacy of labetalol in the treatment of severe hypertension and to characterize those patients (whether their hypertension was severe or moderate) who did not respond to labetalol. From the first patients we have retrospectively selected those with severe hypertension, defined by a supine diastolic BP of 115 mm Hg or more, and those resistant to labetalol defined by a supine diastolic BP of 105 mm Hg or more on a total daily dose of more than 1500 mg. Methods Patients referred to us with hypertension were eligible for the open labetalol study if their ages were in the range yr, the phase four supine diastolic BP was over 110 mm Hg on three occasions on their existing treatment (15 were not receiving any treatment) and there were no contraindications to the use of labetalol. Those who agreed to enter were thereafter seen as outpatients at intervals determined by the patient's response, but not less than every 8 weeks. At each visit the supine and standing BPs were measured by one of us, using a Hawksley random zero sphygmomanometer on the right arm. Labetalol was begun in a dose of 300 mg daily and increased as necessary; other drugs were withdrawn where possible, or added if needed /79/ $01.00 Patients who entered with a mean supine diastolic BP of 115 mm Hg or higher were defined as severely hypertensive. Resistance was defined by a supine diastolic BP greater than 105 mm Hg on two or more occasions while on more than 1500 mg labetalol. The pressures quoted for four of the resistant patients are the means of two or three visits over weeks. The data for patients 23 and 26 are from recordings during one day. All doses are reported as the total daily dose. Haematological, serological and biochemical screening was done on entry and every 3 months thereafter. Most of the patients had mild renal impairment. Four patients were considered to have hypertension caused by renal disease on the basis of clinical and IVP findings, supplemented by renal biopsy in two cases. Low creatinine clearances were thought to be caused by hypertension in other subjects. Side-effects were enquired about and recorded. Paired t tests were used for statistical analysis. Results Severe hypertension (supine diastolic BP > 115 mm Hg) Fourteen of the first labetalol-treated patients were severely hypertensive by this criterion. Two patients who responded well to 300 mg are not discussed further as they died of unrelated diseases within 3 00 Macmillan Journals Ltd 1979

2 1S months. One patient left the study at 2 weeks with no improvement and a fourth (No. 28) was withdrawn after the development of severe postural hypotension at 2 weeks-she is discussed in the next section. The characteristics of the 10 remaining subjects who were followed for at least 6 months are presented in Table 1. It can be seen from Table 2 that most of the patients were well controlled-four of them on labetalol alone and two on labetalol and diuretic only. One patient (No. 7) was not controlled at any time despite doses up to mg and the concurrent use of methyldopa or bethanidine. She and the two others who had poor results despite high doses of labetalol are discussed in the next section. Three other patients were briefly 'uncontrolled', each at one interval only. In two cases previously good control was temporarily lost when the patients reduced their doses, one because she attributed headaches to the drugs. The third patient was controlled by an increased dose of hydrallazine and clonidine, together with labetalol 00 mg. One patient was treated with digoxin for the first 6 months on labetalol. Table 1 Severely hypertensive stolic BP > 115 mm Hg) Age Creatinine clearance Known hypertension Abnormal ECG Previk us stroke Previuus myocardial infarct Previous accelerated hypertension Previous clinical LVF 'Renal' hypertension patients (supine dia- (Mean + s.d.) 6.2 ± 1.8 yr 56.8 ± 33.9 ml/min yr Number One patient with proliferative glomerulonephritis and one with diabetic glomerulosclerosis continued to have increasing creatinine during the study period, and two others with low initial creatinine clearances have subsequently gone on to haemodialysis. The mean increase in serum creatinine in the other patients was 0.02 mm/litre, which is clinically insignificant though unlikely to be a chance finding (P < 0.05). However, they showed no change in mean creatinine clearance. One patient had an antinuclear factor titre of in 20 before the study and 1 in 10 at 12 months; all the other patients had negative tests throughout. There were no other changes in the results of laboratory tests. Resistance to labetalol (supine diastolic BP > 105 mm Hg on > 1500 mg) Six patients were resistant as defined here (Table 3); three had severe hypertension as defined above and are presented first. Patient No. 7 A 0-yr-old West Indian woman with nonnal renal function whose hypertension was discovered in 1972 during pregnancy, had a BP of 256/165 mm Hg on propranolol 160 mg and bendrofluazide 5 mg. She was admitted and started on labetalol while propranolol was withdrawn. On mg her BP was 223/10 mm Hg lying and 206/135 mm Hg standing. Methyldopa 1500 mg was added to give results of 156/ mm Hg and 130/80 mm Hg. Two weeks later the methyldopa was reduced in response to weakness and a large postural fall in BP, 200/120 mm Hg to /70 mm Hg. A further 2 weeks later her BPs were 200/10 mm Hg and 150/120 mm Hg. The methyldopa was then increased Table 2 Labetalol in severe hypertension Labetalol (mg daily) (mean +s.d.) Number on other drugs Patients well controlled Lying BP (mean + s.d.) Standing BP (mean P (paired t tests) s.d) Initial 3 months 6 months 9 months 12 months ± ± /10 6/10 6/10 3/7 2/6 7/10 8/10 /7 5/6 213 ± ± ± ± 17 < J ± NS ± ± ± I NS I L systolic <0.005; diastolic <0.01 lying, < standing

SEVERE & RESISTANT HYPERTENSION 15S while the labetalol was reduced to 1600 mg with no resulting change, and finally bethanidine in a dose of 15 mg replaced the methyldopa giving BPs of 190/120 mm Hg

3 SEVERE & RESISTANT HYPERTENSION 15S while the labetalol was reduced to 1600 mg with no resulting change, and finally bethanidine in a dose of 15 mg replaced the methyldopa giving BPs of 190/120 mm Hg and 130/ mm Hg. It was clear that at times she was not taking the drugs as prescribed, partly because of symptoms of dyspepsia and lassitude, but the consistent presence of postural decreases of BP of at least 30 mm Hg and up to 80 mm Hg is strong evidence that she consumed the larger part of the intended dose. Patient No. 23 A 57-yr-old West Indian man had severe diabetic renal disease, temporal arteritis, long standing hypertension, and dementia. He responded well to labetalol 1800 mg at 3 months when he was also receiving prednisolone, hydrallazine, bumetanide and spironolactone. At 6 months, after the hydrallazine had been withdrawn, his BP had increased to 220/118 mm Hg lying and 218/116 mm Hg standing. Improvement followed re-introduction of the hydrallazine and a decrease in his dosage of prednisolone. It is likely that this man was not always taking his drugs correctly, and his dementia made it impossible to assess his compliance thoroughly. Patient No. 26 A 2-yr-old European man with severe renal impairment had BPs 200/130 mm Hg and 170/120 mm Hg after 3 months when he was taking labetalol mg, prazosin 9 mg and cyclopenthiazide 0.5 mg. He had not had a postural decrease in BP with methyldopa and diuretic, and became dizzy on a higher dose of labetalol. Minoxidil 25 mg reduced his BP to 150/97 mm Hg and 10/95 mm Hg. Three other patients were seen whose BP was resistant to a moderate dose of labetalol. Patient No. A 7-yr-old man with normal kidneys had BPs up to 182/120 mm Hg and 155/97 mm Hg on 1800 mg. His urine sodium was 271 mm/day. His dose was increased to 2200 mg, he was advised to reduce his salt intake, and a diuretic was added. His BPs currently are 123/93 mm Hg and 101/73 mm Hg. Patient No. 10 This 62-yr-old European man had accelerated hypertension, a history of stroke, and probable left Table 3 Resistant patients (diastolic BP>105 mmhg on >1500 mg) Patient BP and treatment (mg daily) No. Severe hypertension (3 patients) 7 Lying 200/10 onlabetalol Standing 150/120 methyidopa amiloride 23 Lying 220/118 labetalol Standing 218/116 bumetanide (prednisolone 26 Lying 200/130 Standing 170/120 labetalol prazosin cyclopenthiazide I nsufficient dose (1 patient) Lying 182/120 onlabetalol Standing 155/97 Limited by postural hypotension (2 patients) 10 Lying 223/111 onlabetalol Standing 178/91 prazosin Later 130/90 hydrallazine frusemide 28 Lying 225/122 onlabetalol Standing 95/60 oxprenolol methyidopa ) 90.5 Subsequent progress 190/120 on labetalol 130/ bethanidine amiloride 185/95 labetalol (sitting) hydrallazine bumetanide (prednisolone 150/97 labetalol 10/95 minoxidil frusemide /93 on labetalol 101/73 bendrofluazide /90 on propranolol prazosin spironolactone hydroflumethiazide (with bilateral above-knee amputations) / on oxprenolol /110 methyldopa 750 amiloride ) variable

16S renal artery stenosis. His control became poor on propranolol, prazosin and hydrallazine. Labetalol mg with prazosin and hydrallazine gave BPs of 223/111 mm Hg and 178/91 mm Hg.

4 16S renal artery stenosis. His control became poor on propranolol, prazosin and hydrallazine. Labetalol mg with prazosin and hydrallazine gave BPs of 223/111 mm Hg and 178/91 mm Hg. He did not have symptoms from this large drop for months, when he was found to become unconscious with a standing BP of 130/90 mm Hg, and labetalol was withdrawn. Soon afterwards a saddle embolus led to bilateral above-knee amputation. Currently his BP is controlled with propranolol, prazosin and a diuretic. Patient No. 28 A 63-yr-old European woman with severe renal failure, previous stroke, and a long history of poorly controlled hypertension, was inadequately controlled on oxprenolol, prazosin and diuretic. Labetalol was started in hospital and increased to 1600 mg, which produced no change in the supine BP, but there was marked postural hypotension-225/122 mm Hg and 95/60 mm Hg. The dose was reduced to 600 mg but she began to fall over so the drug was withdrawn. She had started methyldopa in a dose of 750 mg two days before the falls, and was also receiving oxprenolol 160 mg. This lady did not attend for any follow-up and later was re-admitted with a stroke. Oxprenolol and methyldopa had not improved her supine BP. Discussion Labetalol was an effective drug in most of our severely hypertensive patients. Four were well controlled on this drug alone; two others had added a diuretic; and in two, vasodilators were added. The maximum dose used was 2. g, the mean 1.1 g and the mean in the successful subgroup 975 mg. The diastolic BP for entry to our trial, and the mean dose, are intermediate between those reported by Dargie et al. (1976) (diastolic BP > 120 mm Hg untreated and > 110 mm Hg on previous treatment, 3091 mg) and Pugsley et al. (1976) (diastolic BP > 115 mmhg untreated, 763 mg). Our group differed because we included both untreated and previously treated patients, and diuretics were not used routinely. Bailey (1979) felt that diuretics should be used regularly in hypertensive patients with renal impairment. Seven patients complained of side-effects which were usually transient. However, postural hypotension led to the exclusion of one patient from the trial, and limited the dose of labetalol in two others. Four patients with deteriorating renal function showed expected increases in serum creatinine, and two began regular haemodialysis after more than a year on labetalol. One of these had a creatinine clearance of 8 ml/min at entry to the study, and the other one of 23 ml/min. We found three severe hypertensives and three others who seemed resistant to labetalol. A dose of 1500 mg was used as a criterion because most of our clinic population was found to require < 1500 mg daily, and it exceeded the mean dose used in our 'severe' group. Further, the doses used in patients Nos. 26, 10 and 28 were the maximum tolerated, and we were reluctant to increase the dose for patient No. 7 because of her marked asymptomatic postural hypotension. Similar resistance has been described before. Dargie et al. (1976) had two patients with uncontrolled supine BPs and normal standing BPs who were on 500 mg. Prichard & Boakes (1976) had a patient with BPs of 226/128 mm Hg and 139/98 mm Hg on labetalol mg, with sotalol and a diuretic. One of our patients required only an increased dose and reduction of his salt intake to achieve good control; the five remaining subjects need further explanation. Noncompliance (assessed by tablet counts) could explain some but not all periods of poor control in two patients. Moreover, in all but one patient the postural fall in blood BP was greater on labetalol than on previous therapy and provided evidence that the drug was being taken. We feel that noncompliance cannot explain the resistance of the four remaining patients. For the same reason we feel that variations in drug absorption and metabolism cannot account for refractory supine BP with marked reduction of the standing BP. A central role of the renin system in determining the hypotensive response to propranolol has been proposed by Biihler, et al. (1972) and similar findings have been reported by Karlberg & Tolagen (1976) and Menard et al. (1976). In contrast, no correlation between renin activity and drug effect has been found by Stokes et al. (197), Geyskes et al. (1975) and by Thurston et al. (1978). It is noteworthy that some of the series quoted, both for and against, include patients with renal disease and some include only 'essential' hypertension. Whether or not such a relationship exists, its importance is reduced by the finding of Weber et al. (1977) that the combination of propranolol and diuretic was effective regardless of renin activity. As four of our resistant patients were already taking a diuretic the influence of the renin system alone is unlikely to explain the resistance. Resistance may be due to variation between patients in affinity or number of adrenergic receptors, or to changes in threshold, perhaps dependent on intracellular sodium concentrations; but we have no data to support these speculations in these patients. It may be that elevated BP may be maintained in some patients by an increased cardiac output which cannot be sustained in the erect posture. Alternatively, the partially blocked a- adrenoceptor system may be able to maintain the lying BP on a dose of labetalol which prevents a f,-

5 SEVERE & RESISTANT HYPERTENSION 17S mediated increase in cardiac output on standing. Finally, although we agree with Pugsley et al. (1976) that side-effects tend to disappear, we draw attention to patient No. 10 who suddenly experienced symptoms from severe postural hypotension after four months on an unchanged dose of labetalol. References BAILEY, R.R. (1979). Labetalol in the treatment of patients with hypertension and renal functional impairment. Br. J. clin. Pharmac. 8, suppl. 2, 135S-10S. BOHLER, F.R., LARAGH, J.H., BAER, L., VAUGHAN, E.U. & BRUNNER, H. (1972). Propranolol inhibition of renin secretion: A specific approach to diagnosis and treatment of renin dependent hypertensive diseases. N. Eng. J. Med., 287, DARGIE, H.J., DOLLERY, C.T. & DANIEL, J. (1976). Labetalol in resistant hypertension. Br. J. clin. Pharmac., suppl. 3(), GEYSKES, G.G., BOER, P., VOS, J., LEENAN, F.H.H. & DORHOUR MEES, E.J. (1975). Effect on salt depletion and propranolol on blood pressure and plasma renin activity in various forms of hypertension. Circulat. Res., 36, suppl., 1, I-28-I-256. KARLBERG, B.E. & TOLAGEN, K. (1976). Different antihypertensive effect of beta-blocking drugs in low and normal-high renin hypertension. Am. J. Med., 60, MENARD, J., BERTAGNA, X., N'GUYEN, P.T., DEGOULET, P. CORVOL, C. (1976). Rapid identification of patients with essential hypertension sensitive to acebutolol (a new cardioselective beta-blocker). Am. J. Med., 60, PRICHARD, B.N.C. & BOAKES, A.J. (1976). Labetalol in long term treatment of hypertension. Br. J. clin. Pharmac., suppl., 3(), PUGSLEY, D.J., ARMSTRONG, B.K., NASSIM, M.A. & BEILIN, L.J. (1976). Controlled comparison of labetalol and propranolol in the management of severe hypertension. Br. J. clin. Pharmac., suppl., 3(), STOKES, G.S., WEBBER, M.A. & THORNELL, I.R. (197). Beta-blockers and plasma renin activity in hypertension. Br. Med. J., i, THURSTON, H., BING, R.F., PHOL, J.E.F. & SWALES, JID. (1978). Renin subgroups in essential hypertension: an analysis and critique. Quart. J. Med., 7, WEBER, M.A., LOPEZ-OVEJERO, J.A., DRAYER, J.I., CASE, D.B. & LARAGH, J.H. (1977). Renin reactivity as a determinant of responsiveness to anti-hypertensive treatment. Arch. Intern. Med., 137,

NADOLOL (CORGARD) IN SEVERE AND RESISTANT HYPERTENSION

Med. J. Malaysia Vol. 36 No. 3 September 1981. NADOLOL (CORGARD) IN SEVERE AND RESISTANT HYPERTENSION M.A. SlDEK NONTAK SUMMARY A total of 12 severely hypertensive patients were treated with a once daily