Br. J. clin. Pharmac. (1979), 8, 135S-140S
LABETALOL IN THE TREATMENT OF PATIENTS WITH HYPERTENSION AND RENAL FUNCTIONAL IMPAIRMENT ROSS R. BAILEY Department of Renal Medicine, Christchurch Hospital, Christchurch, New Zealand
1 Labetalol has been used to treat patients with renal hypertension or hypertension in the presence of renal functional impairment. In some patients changes in the glomerular filtration rate (GFR) were followed during the treatment. 2 Sixty patients were treated with labetalol for up to 24 months. Forty-nine of the patients were taking a diuretic and 23 were receiving additional antihypertensive therapy. The antihypertensive effect of labetalol has so far been assessed in 51 patients. Forty-six of these 51 patients have responded with a fall in the mean supine BP from 184/115 to 148/93 mmHg and the mean erect BP from 176/112 to 138/89 mmHg. 3 The mean daily maintenance dose of labetalol for the responders was 418 mg (range 100-1200 mg). The majority of patients were controlled by less than 600 mg daily. 4 Side-effects occurred in 38% of patients, the most serious of which was left ventricular failure in four patients with severe cardiac and renal disease. Other side-effects included transient postural hypotension, scalp tingling and problems with micturition. Fluid retention was frequent but was easily controlled with diuretics. 5 In only three of 31 patients was there a fall in the GFR which could possibly be attributable to the treatment. These changes were small and not clinically significant. An improvement or stabilization of the GFR was noted frequently. 6 Labetalol by intravenous infusion proved disappointing and quite unpredictable in its action. A large single oral dose was effective in hypertensive emergencies. 7 Labetalol, preferably in combination with a diuretic, was a safe and effective drug for patients with hypertension and renal functional impairment.
Introduction LABETALOL hydrochloride is an antihypertensive agent with a unique mode of action involving both aand P-adrenoceptor blockade. The drug lowers BP partly by blocking the oe-adrenoceptors in the peripheral arterioles and thereby lowering the peripheral vascular resistance. The resulting reflex increase in sympathetic drive to the heart is controlled by concurrent blockade of f3-adrenoceptors in the heart (Richards, 1976; Brogden et al., 1978). The haemodynamic effects of labetalol are therefore quite different from those of the pure f,-adrenoceptorblocking drugs and the mechanism for lowering the BP could be generally considered more desirable. Patients with renal disease and renal functional impairment often have hypertension which is difficult to control with antihypertensive drugs (Bailey, 1976). In this context good BP control is essential, so that any further deterioration in renal function can be prevented. 0306-5251/79/170135-06 $01.00
In this study labetalol was used to treat patients with renal hypertension or hypertension in the presence of renal functional impairment. In some patients changes in the glomerular filtration rate (GFR) were followed during the treatment.
Methods
Antihypertensive study Sixty patients (35 male, age range 15-70 yr, mean age 42.6 yr; 25 female, age range 9-60 yr; mean age 39.2 yr with hypertension have been treated with labetalol for up to 24 months. Forty-eight of the 60 patients had a pretreatment plasma creatinine concentration of 0.12 mmol/litre. The mean plasma creatinine for all 60 patients was 0.32 mmol/litre with a range of 0.08-1.39 mmol/litre. © Macmillan Journals Ltd 1979
136S ROSS R. BAILEY
The aetiology of the renal diseases of the patients was as follows: glomerulonephritis 16, essential hypertension 13 (9 with nephrosclerosis), post-renal transplant hypertension 10, renovascular disease 5, reflux nephropathy 5 (1 with malignant hypertension), malignant hypertension 4, lupus nephritis 2 (1 with malignant hypertension), diabetic nephropathy 2, obstructive uropathy 1 (also with malignant hypertension), analgesic nephropathy 1, and polycystic renal disease 1. Forty-nine of the patients were taking a diuretic and 23 were receiving one or more additional antihypertensive agents (prazosin, debrisoquine sulphate, a-methyldopa, timolol, clonidine, verapamil). The starting dose of labetalol was 100 mg orally every 12 hours. The patients were seen at frequent intervals until BP control was obtained; 100 mg dose increments were made as necessary. In all patients a full blood screen, plasma electrolytes, urea, creatinine, liver function tests and antinuclear factor (ANF) were measured every 3 months, or more frequently if necessary. Side-effects were enquired for by asking the patient 'Did the treatment upset you in any way?' Hypertensive emergencies Labetalol was administered intravenously to 13 patients with severe hypertension and a large single oral dose was given to a further five patients.
Effects on glomerular filtration rate In 31 patients the GFR was measured every three months for periods ranging from 3-18 months. GFR was measured using either the single injection 51Cr EDTA clearance method (Bailey et al., 1970) or the mean of two consecutive 24 h creatinine clearance estimations. Results
Antihypertensive study Of the 60 patients treated, the antihypertensive effect of labetalol could be assessed in 51 (Table 1). Six Table 1
patients have not yet responded to treatment, and in three patients it was not possible to assess the effect of the drug because of intolerable side-effects. A 50-yrold woman developed severe postural and exercise dizziness 3 h after each 100 mg dose and lasting for 3-4 hours. After 1 week of treatment she discontinued the medication. Her BP was never measured during one of these dizzy spells. The second patient in whom treatment was not assessable was a 37-yr-old diabetic man with severe hypertension and chronic renal failure who noted difficulty in initiating micturition following the first few doses together with lethargy, listlessness, wheezing, fluid retention and loss of diabetic control. The drug had no effect on the BP after 17 d, when he requested it to be stopped because of the side-effects. The third patient was a 53yr-old man with an anxiety neurosis who was receiving treatment with debrisoquine sulphate and developed failure of ejaculation. His treatment was changed to labetalol but this was associated with impotence and after 29 d he requested a return to his previous therapy. Forty-six of the remaining 51 patients have responded to treatment. Two of the five nonresponders were 63-yr-old men with malignant hypertension and severe generalized vascular disease. One rapidly deteriorated to endstage renal failure requiring regular haemodialysis treatment, and the other failed to respond to labetalol 1600 mg/daily. It was suspected that the latter patient's reliability with his medication was less than ideal. The third patient was a 66-yr-old woman with severe renovascular and cardiovascular disease who developed left ventricular failure on labetalol. The latter was satisfactorily controlled while labetalol was continued but she died suddenly after 137 d of labetalol treatment. The fourth nonresponder was a 39-yr-old woman who developed endstage renal failure due to malignant hypertension and now has a renal transplant which, though functioning well, has a significant stenosis of the graft artery and severe hypertension which has not been controlled by large doses of frusemide, debrisoquine sulphate and labetalol 1200 mg/daily. She has since failed treatment with captopril and is awaiting surgery. The final non-responder was a 40-yr-old
BP response of patients to labetalol therapy
Total number of patients Effect not yet assessable Effect not assessed because of side-effects necessitating labetalol to be stopped Assessed Responders Mean supine BP in responders Mean erect BP in responders
60 6
3 51
46/51 Pre-labetalol 184/115 176/112
When dose stable
148/93 138/89
HYPERTENSION & IMPAIRED RENAL FUNCTION
woman with endstage chronic renal failure due to diabetic nephropathy. Treatment with labetalol for 10 d was ineffective before she was commenced on regular dialysis treatment which controlled her BP. Forty-one of the 60 patients have continued to take labetalol for periods of up to 24 months. The reasons for discontinuing therapy in 19 patients were as follows: 6 required dialysis treatment, 2 developed left ventricular failure, 2 no longer required treatment, 1 died suddenly (details above), 1 patient left the country, 1 suffered severe symptomatic postural hypotension with each 100 mg dose, 1 patient had failure of ejaculation and requested therapy to be stopped, 1 patient with lupus nephritis and severe hypertension developed a reversible deterioration in liver function (plasma bilirubin 9 22jmol/litre; AST 25.69 IU; GGTP 24.129 IU), 1 was troubled by wheeze and fluid retention, 1 developed fluid retention with impotence and requested a return to his former medication, 1 was the diabetic man mentioned above, and a middle-aged man with severe nephrotic syndrome due to focal glomerulosclerosis developed a rash on his face and upper trunk after 4 weeks of treatment. The drug was continued for 3 further weeks and the rash became progressively worse and resembled a severe seborrhoeic dermatitis. The rash cleared within 1 week of stopping labetalol. It was not possible to rechallenge him with labetalol as he died 2 months later following a severe septicaemic illness while being treated with corticosteroids for his renal disease. Among the 46 patients who have responded to labetalol to date the mean maintenance daily dose was 418 mg with a range of 100-1200 mg daily. Forty of these 46 patients required 600 mg daily or less.
The mean supine BP before labetalol was introduced in these 46 responders was 184/115 and when the dose was stable the mean value fell to 148/93 mmHg. The mean values in the erect position were 176/112 and 138/89 mmHg, respectively. Thirtynine of these patients had their diastolic BP consistently lowered to 100 mmHg or less. Side-effects and toxic effects
Thirty-seven of the 60 patients (62%) had no sideeffects which could be attributable to labetalol therapy. The side-effects noted are included in Table 2. The most important included the precipitation of left ventricular failure in four patients with severe coexisting cardiac disease and renal failure. In two patients the failure was controlled and labetalol continued. One of these later died suddenly (details above). In one woman the onset of failure was fulminating and required immediate dialysis with ultrafiltration as large doses of frusemide, venesection and rotating limb tourniquets were unsuccessful. Several patients reported postural dizziness for 1-3 h after the first few doses. Six patients have developed weakly positive antinuclear factors after 6-18 months of treatment. Labetalol in hypertensive emergencies Labetalol has been administered intravenously to 13 patients with hypertensive emergencies. A young girl with multiple phaeochromocytomata was well controlled and will be reported separately (Bailey, 1979). Of the other 12 patients only three responded, and these could only be classified as partial responses.
Table 2 Side-effects attributable to labetalol therapy
Side-effect Nil Acute left ventricular failure Postural dizziness Fluid retention Irritability, insomnia and lethargy Bizarre behaviour and flippant attitude
Listless, loss of diabetic control, wheezing, inability to void urine, fluid retention Scalp tingling, migrainous aura, lethargy (transient) Failure of ejaculation, fluid retention Diarrhoea (early) and later onset of wheeze and fluid retention Slowing of the urinary stream Impotence, fluid retention and sweating Skin tingling, headache and slowing of the urinary stream Rash on face and upper trunk Worsening of asthma Unable to tolerate taste of drug Derangement of liver function (lupus patient)
137S
Number 37 4 4 2 1
(62%) (1 sudden death) (disappeared when dose reduced)
1
(disappeared when dose reduced)
1 1 1
1 1 1 1 1 1 1 1
(settled when drug stopped) (fatal myocardial infarction 11 days after stopping drug)
(reversible)
138S
ROSS R. BAILEY
a c
0 *0;
E01
e
o
0
J
.
1400
.
1600
2. 1800
.5.
.
.
2000
2200
Time (h) Figure 1 Falrin BP seen in a 54-yr-old woman, with severe hypertension and a nephrotic syndrome, who was given a single 300 mg oral dose of labetalol.
These three patients were the only ones who had not received any other antihypertensive drug. Doses of 0.7-1.5 mg/kg by intravenous bolus injection were unsuccessful. Labetalol given by a continuous infusion starting at 20 mg/h and doubling the dose each hour as necessary proved more effective. Intravenous infusion of labetalol caused severe scalp tingling in a woman who also later reported it after commencing the drug orally. Two men reported a sudden urge to void urine but an inability to do so, and one of these also noted a 'prickly' sensation all over his body. Another patient complained of facial
flushing and light headedness. Single oral doses of 300-400 mg proved effective within 1-2 h for controlling severe hypertension before renal biopsy (2 patients), renal angiography (1 patient), in a 49-yr-old man whose BP rose rapidly 36 h after renal transplantation and in a 54-yr-old Table 3 Renal function (mean values and range of values) in 31 patients treated with labetalol and followed for 3-18 months) Test
Pre-labetalol
End of followup
period Plasma urea (mmol/litre) Plasma creatinine (mmol/litre) GFR
10.1 (3.4-42.6) 11.9 (4.1-44.5) 0.19 (0.08-0.52) 0.25 (0.08-1.17) 0.98 (0.08-2.35) 0.97 (0.03-2.43)
I
o
0
L
6
a
.
.
12
s
18
Months of treatment Figure 2 Changes in GFR in 31 patients taking labetalol and followed for 3-18 months. The nine patients denoted had essential hypertension (0-0).
woman with a nephrotic syndrome (Figure 1). None of these patients complained of side-effects.
Effects on glomerularfiltration rate The mean values for the plasma urea, creatinine and GFR in the 31 patients studied are included in Table 3. In ten patients the GFR did not change, in ten there was a significant improvement (six had essential hypertension) and in the remaining eleven patients there was a deterioration (Figure 2). Four of the latter had progressive glomerulonephritis, three chronic transplant rejection, three essential hypertension and one reflux nephropathy. The nine patients in this group with essential hypertension were followed for 6-18 months (mean 12.3 months). The mean plasma urea before labetalol was started was 10.0 mmol/litre, the mean plasma creatinine 0.19 mmol/litre and the mean GFR 0.21 ml/second. The mean values at the end of the study period were 10.0 mmol/litre, 0.18 mmol/litre and 1.24 ml/s, respectively. In six of these nine patients the GFR improved, and in the remaining three a small fall was noted despite good BP control (2.30 1.82 ml/s over 18 months; 1.78 1.58 ml/s over 12 months; and 0.77 0.58 over 10 months; Figure 2).
HYPERTENSION & IMPAIRED RENAL FUNCTION
Discussion In this study, labetalol has proved to be a very effective antihypertensive agent in patients with moderate or severe hypertension and renal functional impairment. The most important side-effect was the precipitation of cardiac failure in four patients with severe coexisting cardiac disease and renal failure. Labetalol, like the pure fl-adrenoceptor-blocking drugs, should be used with caution in patients with uncontrolled cardiac failure and in those with a history of asthma or chronic obstructive airways disease. Another important side-effect was postural hypotension occurring 1-3 h after a dose. However, this seemed to be related to an excessive commencing dose of the drug. One patient was extremely sensitive to labetalol and a dose of 50 mg every 12 h was all that was necessary. Postural hypotension was more of a problem in the elderly and in patients on high doses of potent diuretics or adrenergic neurone-blocking drugs. It could also be expected to be more troublesome in diabetic patients with autonomic neuropathy. If labetalol was used without a diuretic then fluid retention was likely to occur. However, this was no different to that seen with any other effective antihypertensive agent. This fluid retention was insufficient to cause clinical oedema but was manifest as a 1-3 kg weight increase usually with a loss of BP control which was only regained by introducing a diuretic. It is strongly suggested that all patients have their body weight monitored closely and if BP control is lost it would be more rational to add, or increase, the diuretic dose, or commence some dietary sodium restriction rather than increase the dose of labetalol. Until more information is available, the drug should be used with care in insulin-requiring diabetics. The unusual side-effects of transient scalp, or generalized skin tingling occurring at the commencement of treatment is a real entity, as is the problem with slowing of the urinary stream and occasionally an inability to void urine despite a strong urge to do so (Bailey, 1977). The latter side-effect, although uncommon, may prove to be troublesome in men with prostatism. It is possibly due to an action on the a-adrenoceptors which are predominantly in the bladder base and urethra where they control bladder outlet and urethral pressure and are therefore in part responsible for urinary continence. The half-life of labetalol is unaltered in renal failure (Thompson et al., 1977). The present study has confirmed the author's earlier observations (Bailey, 1978) that labetalol was effective and safe even in the presence of severe renal failure. The drug did not seem to cause any significant deterioration in the GFR of those patients whose renal function was monitored closely, and in the majority of those whose
139S
renal functional impairment was due to hypertension alone a considerable improvement in GFR was observed. These observations confirm those made by Thompson et al. (1977) and Williams et al. (1978). These findings are in sharp contrast to those with the pure fl-adrenoceptor-blocking drugs which by their action in lowering cardiac output may also lead to a fall in renal blood flow and GFR (Ibsen & SederbergOlsen, 1973; Bailey, 1976). The latter may be clinically significant in patients with moderate or severely impaired renal function and is becoming an increasing source of concern to nephrologists (Begg et al., 1979). Six patients developed a weakly positive titre of ANF but in none was there an abnormal titre of DNA antibodies or any clinical features suggestive of disseminated lupus erythematosus. Labetalol was highly effective in two young women with severe hypertension secondary to lupus nephritis and did not cause a flare-up in the disease, although it was later necessary to discontinue the drug in one of these patients because of a disturbance in her liver function tests. Several patients when switched from a ,Badrenoceptor blocker to labetalol noted an increase in exercise tolerance and a loss of their 'body and skin coldness', and several patients reported an improved effort tolerance. In this study the majority of patients were controlled on less than 600 mg labetalol daily. In only one patient was a beneficial effect seen when the daily dose of labetalol was increased above 800 mg. When administered intravenously, labetalol proved disappointing because of its frequent failure when given to patients who had been taking other antihypertensive drugs and also because of its quite unpredictable action. It would seem preferable to use an intravenous infusion of labetalol starting with a dose of 20 mg/h and doubling the dose each hour until an effect is obtained. In the author's experience intravenous labetalol is inferior to intravenous diazoxide for the treatment of hypertensive emergencies, but the former drug does not result in any significant secondary cardiodynamic changes such as tachycardia or an increase in cardiac output. More recently a 'single oral dose of 300-400 mg labetalol has been found to be effective in rapidly controlling severe hypertension. Similar results have been reported by Ghose et al. (1978). Labetalol seems to be an effective drug when given alone, or preferably with a diuretic, to patients with hypertension and impaired renal function.
I thank Dr D.S.P. Dickson, Medical Adviser, Allen & Hanburys, Palmerston North, New Zealand, for his assistance. Miss Susan Small and Mrs Zita Moody prepared
the manuscript.
140S
ROSS R. BAILEY
References BAILEY, R.R., ROGERS, T.G.H. & TAIT, J.J. (1970).
therapeutic use in hypertension. Drugs, 15, 251-270.
Measurement of glomerular filtration rate using a single injection of 51Cr-edetic acid. Aust. Ann. Med., 19, 255-258. BAILEY, R.R. (1976). The kidney and antihypertensive therapy. Drugs, 11, suppl. 1, 70-77. BAILEY, R.R. (1978). Labetalol in the treatment of patients with hypertension and renal functional impairment. Abstr. VII World Congr. Cardiol., Tokyo, No. 1040. BAILEY, R.R. (1979). Labetalol in the treatment of hypertension: A case report. Br. J. clin. Pharmac. 8, suppl. 2, 141S-142S. BEGG, E., MUNN, S. & BAILEY, R.R. (1979). Acebutolol in the treatment of patients with hypertension and renal functional impairment. New Zealand med. J. (in press).
GHOSE, R.R., MATHUR, Y.B., UPADHYAY, M., MORGAN,
BROGDEN, R.N. HEEL, R.C., SPEIGHT, T.M. & AVERY, G.S.
(1978). Labetalol: a review of its pharmacology and
W.D., KHAN, S. (1978). Treatment of hypertensive emergencies with oral labetalol. Br. med. J., 2, 96. IBSEN, H. & SEDERBERG-OLSEN, P. (1973). Changes in glomerular filtration rate during long-term treatment with propranolol in patients with arterial hypertension. Clin. Sci., 44, 129-134. RICHARDS, D.A. (1976). Pharmacological effects of labetalol in man. Br. J. clin. Pharmac., 3, 721-723. THOMPSON, F.D., JOEKES, A.M. & HUSSEIN, M.M. (1977). Labetalol used as a hypotensive agent in the presence of renal disease. Kid. Int., 11, 287-288. WILLIAMS, J.G., VOSS, K.D. & CRASWELL, P.W. (1978).
Labetalol in the treatment of hypertensive renal patients. Med. J. Aust., 1, 225-228.
LABETALOL IN THE TREATMENT OF PATIENTS WITH HYPERTENSION AND RENAL FUNCTIONAL IMPAIRMENT ROSS R. BAILEY Department of Renal Medicine, Christchurch Hospital, Christchurch, New Zealand
1 Labetalol has been used to treat patients with renal hypertension or hypertension in the presence of renal functional impairment. In some patients changes in the glomerular filtration rate (GFR) were followed during the treatment. 2 Sixty patients were treated with labetalol for up to 24 months. Forty-nine of the patients were taking a diuretic and 23 were receiving additional antihypertensive therapy. The antihypertensive effect of labetalol has so far been assessed in 51 patients. Forty-six of these 51 patients have responded with a fall in the mean supine BP from 184/115 to 148/93 mmHg and the mean erect BP from 176/112 to 138/89 mmHg. 3 The mean daily maintenance dose of labetalol for the responders was 418 mg (range 100-1200 mg). The majority of patients were controlled by less than 600 mg daily. 4 Side-effects occurred in 38% of patients, the most serious of which was left ventricular failure in four patients with severe cardiac and renal disease. Other side-effects included transient postural hypotension, scalp tingling and problems with micturition. Fluid retention was frequent but was easily controlled with diuretics. 5 In only three of 31 patients was there a fall in the GFR which could possibly be attributable to the treatment. These changes were small and not clinically significant. An improvement or stabilization of the GFR was noted frequently. 6 Labetalol by intravenous infusion proved disappointing and quite unpredictable in its action. A large single oral dose was effective in hypertensive emergencies. 7 Labetalol, preferably in combination with a diuretic, was a safe and effective drug for patients with hypertension and renal functional impairment.
Introduction LABETALOL hydrochloride is an antihypertensive agent with a unique mode of action involving both aand P-adrenoceptor blockade. The drug lowers BP partly by blocking the oe-adrenoceptors in the peripheral arterioles and thereby lowering the peripheral vascular resistance. The resulting reflex increase in sympathetic drive to the heart is controlled by concurrent blockade of f3-adrenoceptors in the heart (Richards, 1976; Brogden et al., 1978). The haemodynamic effects of labetalol are therefore quite different from those of the pure f,-adrenoceptorblocking drugs and the mechanism for lowering the BP could be generally considered more desirable. Patients with renal disease and renal functional impairment often have hypertension which is difficult to control with antihypertensive drugs (Bailey, 1976). In this context good BP control is essential, so that any further deterioration in renal function can be prevented. 0306-5251/79/170135-06 $01.00
In this study labetalol was used to treat patients with renal hypertension or hypertension in the presence of renal functional impairment. In some patients changes in the glomerular filtration rate (GFR) were followed during the treatment.
Methods
Antihypertensive study Sixty patients (35 male, age range 15-70 yr, mean age 42.6 yr; 25 female, age range 9-60 yr; mean age 39.2 yr with hypertension have been treated with labetalol for up to 24 months. Forty-eight of the 60 patients had a pretreatment plasma creatinine concentration of 0.12 mmol/litre. The mean plasma creatinine for all 60 patients was 0.32 mmol/litre with a range of 0.08-1.39 mmol/litre. © Macmillan Journals Ltd 1979
136S ROSS R. BAILEY
The aetiology of the renal diseases of the patients was as follows: glomerulonephritis 16, essential hypertension 13 (9 with nephrosclerosis), post-renal transplant hypertension 10, renovascular disease 5, reflux nephropathy 5 (1 with malignant hypertension), malignant hypertension 4, lupus nephritis 2 (1 with malignant hypertension), diabetic nephropathy 2, obstructive uropathy 1 (also with malignant hypertension), analgesic nephropathy 1, and polycystic renal disease 1. Forty-nine of the patients were taking a diuretic and 23 were receiving one or more additional antihypertensive agents (prazosin, debrisoquine sulphate, a-methyldopa, timolol, clonidine, verapamil). The starting dose of labetalol was 100 mg orally every 12 hours. The patients were seen at frequent intervals until BP control was obtained; 100 mg dose increments were made as necessary. In all patients a full blood screen, plasma electrolytes, urea, creatinine, liver function tests and antinuclear factor (ANF) were measured every 3 months, or more frequently if necessary. Side-effects were enquired for by asking the patient 'Did the treatment upset you in any way?' Hypertensive emergencies Labetalol was administered intravenously to 13 patients with severe hypertension and a large single oral dose was given to a further five patients.
Effects on glomerular filtration rate In 31 patients the GFR was measured every three months for periods ranging from 3-18 months. GFR was measured using either the single injection 51Cr EDTA clearance method (Bailey et al., 1970) or the mean of two consecutive 24 h creatinine clearance estimations. Results
Antihypertensive study Of the 60 patients treated, the antihypertensive effect of labetalol could be assessed in 51 (Table 1). Six Table 1
patients have not yet responded to treatment, and in three patients it was not possible to assess the effect of the drug because of intolerable side-effects. A 50-yrold woman developed severe postural and exercise dizziness 3 h after each 100 mg dose and lasting for 3-4 hours. After 1 week of treatment she discontinued the medication. Her BP was never measured during one of these dizzy spells. The second patient in whom treatment was not assessable was a 37-yr-old diabetic man with severe hypertension and chronic renal failure who noted difficulty in initiating micturition following the first few doses together with lethargy, listlessness, wheezing, fluid retention and loss of diabetic control. The drug had no effect on the BP after 17 d, when he requested it to be stopped because of the side-effects. The third patient was a 53yr-old man with an anxiety neurosis who was receiving treatment with debrisoquine sulphate and developed failure of ejaculation. His treatment was changed to labetalol but this was associated with impotence and after 29 d he requested a return to his previous therapy. Forty-six of the remaining 51 patients have responded to treatment. Two of the five nonresponders were 63-yr-old men with malignant hypertension and severe generalized vascular disease. One rapidly deteriorated to endstage renal failure requiring regular haemodialysis treatment, and the other failed to respond to labetalol 1600 mg/daily. It was suspected that the latter patient's reliability with his medication was less than ideal. The third patient was a 66-yr-old woman with severe renovascular and cardiovascular disease who developed left ventricular failure on labetalol. The latter was satisfactorily controlled while labetalol was continued but she died suddenly after 137 d of labetalol treatment. The fourth nonresponder was a 39-yr-old woman who developed endstage renal failure due to malignant hypertension and now has a renal transplant which, though functioning well, has a significant stenosis of the graft artery and severe hypertension which has not been controlled by large doses of frusemide, debrisoquine sulphate and labetalol 1200 mg/daily. She has since failed treatment with captopril and is awaiting surgery. The final non-responder was a 40-yr-old
BP response of patients to labetalol therapy
Total number of patients Effect not yet assessable Effect not assessed because of side-effects necessitating labetalol to be stopped Assessed Responders Mean supine BP in responders Mean erect BP in responders
60 6
3 51
46/51 Pre-labetalol 184/115 176/112
When dose stable
148/93 138/89
HYPERTENSION & IMPAIRED RENAL FUNCTION
woman with endstage chronic renal failure due to diabetic nephropathy. Treatment with labetalol for 10 d was ineffective before she was commenced on regular dialysis treatment which controlled her BP. Forty-one of the 60 patients have continued to take labetalol for periods of up to 24 months. The reasons for discontinuing therapy in 19 patients were as follows: 6 required dialysis treatment, 2 developed left ventricular failure, 2 no longer required treatment, 1 died suddenly (details above), 1 patient left the country, 1 suffered severe symptomatic postural hypotension with each 100 mg dose, 1 patient had failure of ejaculation and requested therapy to be stopped, 1 patient with lupus nephritis and severe hypertension developed a reversible deterioration in liver function (plasma bilirubin 9 22jmol/litre; AST 25.69 IU; GGTP 24.129 IU), 1 was troubled by wheeze and fluid retention, 1 developed fluid retention with impotence and requested a return to his former medication, 1 was the diabetic man mentioned above, and a middle-aged man with severe nephrotic syndrome due to focal glomerulosclerosis developed a rash on his face and upper trunk after 4 weeks of treatment. The drug was continued for 3 further weeks and the rash became progressively worse and resembled a severe seborrhoeic dermatitis. The rash cleared within 1 week of stopping labetalol. It was not possible to rechallenge him with labetalol as he died 2 months later following a severe septicaemic illness while being treated with corticosteroids for his renal disease. Among the 46 patients who have responded to labetalol to date the mean maintenance daily dose was 418 mg with a range of 100-1200 mg daily. Forty of these 46 patients required 600 mg daily or less.
The mean supine BP before labetalol was introduced in these 46 responders was 184/115 and when the dose was stable the mean value fell to 148/93 mmHg. The mean values in the erect position were 176/112 and 138/89 mmHg, respectively. Thirtynine of these patients had their diastolic BP consistently lowered to 100 mmHg or less. Side-effects and toxic effects
Thirty-seven of the 60 patients (62%) had no sideeffects which could be attributable to labetalol therapy. The side-effects noted are included in Table 2. The most important included the precipitation of left ventricular failure in four patients with severe coexisting cardiac disease and renal failure. In two patients the failure was controlled and labetalol continued. One of these later died suddenly (details above). In one woman the onset of failure was fulminating and required immediate dialysis with ultrafiltration as large doses of frusemide, venesection and rotating limb tourniquets were unsuccessful. Several patients reported postural dizziness for 1-3 h after the first few doses. Six patients have developed weakly positive antinuclear factors after 6-18 months of treatment. Labetalol in hypertensive emergencies Labetalol has been administered intravenously to 13 patients with hypertensive emergencies. A young girl with multiple phaeochromocytomata was well controlled and will be reported separately (Bailey, 1979). Of the other 12 patients only three responded, and these could only be classified as partial responses.
Table 2 Side-effects attributable to labetalol therapy
Side-effect Nil Acute left ventricular failure Postural dizziness Fluid retention Irritability, insomnia and lethargy Bizarre behaviour and flippant attitude
Listless, loss of diabetic control, wheezing, inability to void urine, fluid retention Scalp tingling, migrainous aura, lethargy (transient) Failure of ejaculation, fluid retention Diarrhoea (early) and later onset of wheeze and fluid retention Slowing of the urinary stream Impotence, fluid retention and sweating Skin tingling, headache and slowing of the urinary stream Rash on face and upper trunk Worsening of asthma Unable to tolerate taste of drug Derangement of liver function (lupus patient)
137S
Number 37 4 4 2 1
(62%) (1 sudden death) (disappeared when dose reduced)
1
(disappeared when dose reduced)
1 1 1
1 1 1 1 1 1 1 1
(settled when drug stopped) (fatal myocardial infarction 11 days after stopping drug)
(reversible)
138S
ROSS R. BAILEY
a c
0 *0;
E01
e
o
0
J
.
1400
.
1600
2. 1800
.5.
.
.
2000
2200
Time (h) Figure 1 Falrin BP seen in a 54-yr-old woman, with severe hypertension and a nephrotic syndrome, who was given a single 300 mg oral dose of labetalol.
These three patients were the only ones who had not received any other antihypertensive drug. Doses of 0.7-1.5 mg/kg by intravenous bolus injection were unsuccessful. Labetalol given by a continuous infusion starting at 20 mg/h and doubling the dose each hour as necessary proved more effective. Intravenous infusion of labetalol caused severe scalp tingling in a woman who also later reported it after commencing the drug orally. Two men reported a sudden urge to void urine but an inability to do so, and one of these also noted a 'prickly' sensation all over his body. Another patient complained of facial
flushing and light headedness. Single oral doses of 300-400 mg proved effective within 1-2 h for controlling severe hypertension before renal biopsy (2 patients), renal angiography (1 patient), in a 49-yr-old man whose BP rose rapidly 36 h after renal transplantation and in a 54-yr-old Table 3 Renal function (mean values and range of values) in 31 patients treated with labetalol and followed for 3-18 months) Test
Pre-labetalol
End of followup
period Plasma urea (mmol/litre) Plasma creatinine (mmol/litre) GFR
10.1 (3.4-42.6) 11.9 (4.1-44.5) 0.19 (0.08-0.52) 0.25 (0.08-1.17) 0.98 (0.08-2.35) 0.97 (0.03-2.43)
I
o
0
L
6
a
.
.
12
s
18
Months of treatment Figure 2 Changes in GFR in 31 patients taking labetalol and followed for 3-18 months. The nine patients denoted had essential hypertension (0-0).
woman with a nephrotic syndrome (Figure 1). None of these patients complained of side-effects.
Effects on glomerularfiltration rate The mean values for the plasma urea, creatinine and GFR in the 31 patients studied are included in Table 3. In ten patients the GFR did not change, in ten there was a significant improvement (six had essential hypertension) and in the remaining eleven patients there was a deterioration (Figure 2). Four of the latter had progressive glomerulonephritis, three chronic transplant rejection, three essential hypertension and one reflux nephropathy. The nine patients in this group with essential hypertension were followed for 6-18 months (mean 12.3 months). The mean plasma urea before labetalol was started was 10.0 mmol/litre, the mean plasma creatinine 0.19 mmol/litre and the mean GFR 0.21 ml/second. The mean values at the end of the study period were 10.0 mmol/litre, 0.18 mmol/litre and 1.24 ml/s, respectively. In six of these nine patients the GFR improved, and in the remaining three a small fall was noted despite good BP control (2.30 1.82 ml/s over 18 months; 1.78 1.58 ml/s over 12 months; and 0.77 0.58 over 10 months; Figure 2).
HYPERTENSION & IMPAIRED RENAL FUNCTION
Discussion In this study, labetalol has proved to be a very effective antihypertensive agent in patients with moderate or severe hypertension and renal functional impairment. The most important side-effect was the precipitation of cardiac failure in four patients with severe coexisting cardiac disease and renal failure. Labetalol, like the pure fl-adrenoceptor-blocking drugs, should be used with caution in patients with uncontrolled cardiac failure and in those with a history of asthma or chronic obstructive airways disease. Another important side-effect was postural hypotension occurring 1-3 h after a dose. However, this seemed to be related to an excessive commencing dose of the drug. One patient was extremely sensitive to labetalol and a dose of 50 mg every 12 h was all that was necessary. Postural hypotension was more of a problem in the elderly and in patients on high doses of potent diuretics or adrenergic neurone-blocking drugs. It could also be expected to be more troublesome in diabetic patients with autonomic neuropathy. If labetalol was used without a diuretic then fluid retention was likely to occur. However, this was no different to that seen with any other effective antihypertensive agent. This fluid retention was insufficient to cause clinical oedema but was manifest as a 1-3 kg weight increase usually with a loss of BP control which was only regained by introducing a diuretic. It is strongly suggested that all patients have their body weight monitored closely and if BP control is lost it would be more rational to add, or increase, the diuretic dose, or commence some dietary sodium restriction rather than increase the dose of labetalol. Until more information is available, the drug should be used with care in insulin-requiring diabetics. The unusual side-effects of transient scalp, or generalized skin tingling occurring at the commencement of treatment is a real entity, as is the problem with slowing of the urinary stream and occasionally an inability to void urine despite a strong urge to do so (Bailey, 1977). The latter side-effect, although uncommon, may prove to be troublesome in men with prostatism. It is possibly due to an action on the a-adrenoceptors which are predominantly in the bladder base and urethra where they control bladder outlet and urethral pressure and are therefore in part responsible for urinary continence. The half-life of labetalol is unaltered in renal failure (Thompson et al., 1977). The present study has confirmed the author's earlier observations (Bailey, 1978) that labetalol was effective and safe even in the presence of severe renal failure. The drug did not seem to cause any significant deterioration in the GFR of those patients whose renal function was monitored closely, and in the majority of those whose
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renal functional impairment was due to hypertension alone a considerable improvement in GFR was observed. These observations confirm those made by Thompson et al. (1977) and Williams et al. (1978). These findings are in sharp contrast to those with the pure fl-adrenoceptor-blocking drugs which by their action in lowering cardiac output may also lead to a fall in renal blood flow and GFR (Ibsen & SederbergOlsen, 1973; Bailey, 1976). The latter may be clinically significant in patients with moderate or severely impaired renal function and is becoming an increasing source of concern to nephrologists (Begg et al., 1979). Six patients developed a weakly positive titre of ANF but in none was there an abnormal titre of DNA antibodies or any clinical features suggestive of disseminated lupus erythematosus. Labetalol was highly effective in two young women with severe hypertension secondary to lupus nephritis and did not cause a flare-up in the disease, although it was later necessary to discontinue the drug in one of these patients because of a disturbance in her liver function tests. Several patients when switched from a ,Badrenoceptor blocker to labetalol noted an increase in exercise tolerance and a loss of their 'body and skin coldness', and several patients reported an improved effort tolerance. In this study the majority of patients were controlled on less than 600 mg labetalol daily. In only one patient was a beneficial effect seen when the daily dose of labetalol was increased above 800 mg. When administered intravenously, labetalol proved disappointing because of its frequent failure when given to patients who had been taking other antihypertensive drugs and also because of its quite unpredictable action. It would seem preferable to use an intravenous infusion of labetalol starting with a dose of 20 mg/h and doubling the dose each hour until an effect is obtained. In the author's experience intravenous labetalol is inferior to intravenous diazoxide for the treatment of hypertensive emergencies, but the former drug does not result in any significant secondary cardiodynamic changes such as tachycardia or an increase in cardiac output. More recently a 'single oral dose of 300-400 mg labetalol has been found to be effective in rapidly controlling severe hypertension. Similar results have been reported by Ghose et al. (1978). Labetalol seems to be an effective drug when given alone, or preferably with a diuretic, to patients with hypertension and impaired renal function.
I thank Dr D.S.P. Dickson, Medical Adviser, Allen & Hanburys, Palmerston North, New Zealand, for his assistance. Miss Susan Small and Mrs Zita Moody prepared
the manuscript.
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ROSS R. BAILEY
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