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Aims: Several antihypertensive drugs are used in the treatment of severe hypertension in pregnancy. The present study is a network meta-analysis comparing the efficacy and safety of these drugs., Methods: Electronic databases were searched for randomized clinical trials comparing drugs used in the treatment of severe hypertension in pregnancy. The number of women achieving the target blood pressure (BP) was the primary outcome. Doses required and time taken for achieving the target BP, failure rate, and incidences of maternal tachycardia, palpitation, hypotension, headache, and neonatal death and stillbirth were the secondary outcomes. Mixed treatment comparison pooled estimates were generated using a random-effects model. Odds ratios for the categorical and mean difference for the numerical outcomes were the effect estimates., Results: Fifty-one studies were included in the systematic review and 46 in the meta-analysis. No significant differences in the number of patients achieving target BP was observed between any of the drugs. Diazoxide [-15 (-20.6, -9.4)], nicardipine [-11.8 (-22.3, -1.2)], nifedipine/celastrol [-19.3 (-27.4, -11.1)], nifedipine/vitamin D [-17.1 (-25.7, -9.7)], nifedipine/resveratrol [-13.9 (-22.6, -5.2)] and glyceryl trinitrate [-33.8 (-36.7, -31)] were observed to achieve the target BP (in minutes) more rapidly than hydralazine. Nifedipine required fewer doses than hydralazine for achieving the target BP. Glyceryl trinitrate and labetalol were associated with fewer incidences of tachycardia and palpitation respectively than hydralazine. Trial sequential analysis concluded adequate evidence for hydralazine and nifedipine compared with labetalol. Moderate quality of evidence was observed for direct comparison estimate between labetalol and hydralazine but was either low or very low for other comparisons., Conclusion: The present evidence suggests similar efficacy between nifedipine, hydralazine and labetalol in the treatment of severe hypertension in pregnancy. Subtle differences may exist in their safety profile. The evidence is inadequate for other drugs., (© 2018 The British Pharmacological Society.)

The effects of sulindac and indomethacin on the blood pressure response to labetalol were determined in well-controlled predominantly obese hypertensive patients (n = 26). A stabilized dose of labetalol alone was administered on weeks 1 and 3, and either indomethacin or sulindac was administered with labetalol on week 2, with cross-over to the other drug on week 4. Indomethacin and sulindac increased the sitting and standing systolic blood pressure (BP) to a statistically significant extent compared with placebo. The effects of indomethacin on systolic BP, diastolic BP, and weight were not significantly different from those with sulindac. Indomethacin but not sulindac produced minor increases in diastolic BP and weight compared with placebo.

1. The antihypertensive effect of dilevalol, a compound which combines beta-adrenoceptor blocking and vasodilating properties due to beta 2-adrenoceptor agonism, was studied in nineteen patients with isolated systolic hypertension (ISH). A randomized, double-blind, placebo-controlled, cross-over trial with two 4 week treatment periods was used to compare the efficacy of once daily dosing with dilevalol (in the range of 100-400 mg daily) against placebo. Assessment of response involved both casual blood pressure readings (amongst all patients) and 24 h ambulatory blood pressure monitoring (in ten of the nineteen patients). 2. A mean fall of 12/5 mm Hg (s.e. mean 3/2, P less than 0.05) and 9/3 mm Hg (s.e. mean 3/2, P less than 0.05) in supine and standing blood pressure respectively was observed with dilevalol. Mean heart rate was unchanged. The ambulatory monitoring profile demonstrated a smaller reduction in mean blood pressure (7/8 mm Hg) over the 24 h period and a reduction of 10/11 mm Hg over the daytime period. A blunting of the early morning increase in systolic pressure was observed with dilevalol. 3. The drug was well tolerated with light headedness and lethargy being reported more commonly than with placebo. Biochemical parameters were unaffected. 4. It is concluded that dilevalol in the doses used has a small but measurable antihypertensive effect as monotherapy in the treatment of ISH.

1 The anti-hypertensive effects of labetalol have been compared and contrasted with other groups of anti-hypertensive drugs in this review of the published literature. 2 The data show that the pharmacological and haemodynamic profile of labetalol in man is distinctly different from that of other specific anti-hypertensive agents; namely the properties of competitive alpha-and beta-adrenoceptor blockade leading to haemodynamic effects of reduced blood pressure and peripheral vascular resistance with little accompanying changes in resting heart rate or cardiac output. 3 The anti-hypertensive effects of labetalol are dose related. In fixed dose comparative studies equivalent anti-hypertensive effects to those of labetalol have been shown for individual drugs of the beta-adrenoceptor-blocking and diuretic groups. In dose titration studies, equivalent anti-hypertensive effects at given doses of labetalol have been demonstrated for drugs of the following types: beta-adrenoceptor blockers, beta-blockers plus diuretics, methyldopa, adrenergic neurone blockers and the combination of beta-blockers plus a peripheral vasodilator. 4 Comparing side-effect liabilities, it is clear that quantitatively labetalol produces no greater burden of side-effects than drugs of the beta-adrenoceptor-blocking group. Qualitative differences, however, do exist; in particular, symptomatic postural hypotension is dose related and is more likely to occur when excessive doses (greater than 2 g daily) are used.

1 Labetalol has been used to treat 163 patients at the Dunedin Hypertension Clinic for periods up to 6.5 y, and of 128 patients in a New Zealand multicentre study for 2 yr. 2 Labetalol was often effective when other anti-hypertensive agents, including beta-blockers, had failed. It was usually given with a diuretic. 3 Mean daily dose was 700 mg (range 100-2400 mg). No tolerance to the anti-hypertensive effect was seen. 4 Some postural-induced decrease in blood pressure on labetalol was common. 5 Side-effects led to withdrawal of labetalol in about 25% of patients, mainly during the first few months of therapy. Another 25% had minor side-effects but could continue with the drug. 6 There were three types of side-effects (in order of frequency): (a) non-specific, (b) related to alpha-blockade and (c) related to beta-blockade. The latter were much less troublesome than on "pure" beta-blockers. 7 There was no significant evidence of renal haematological or hepatic toxicity. 8 Anti-nuclear antibody tests became positive on labetalol in about 15%, usually at low titres but in one patient the titre increased to a high level and fell when labetalol was stopped. 9 In a subset of 25 patients who took labetalol for the longest time (up to 6.5 yr) there was a 16% incidence of anti-mitochondrial antibodies.

1 Labetalol, a hypotensive agent combining alpha- and beta-adrenoceptor antagonist properties, was used to treat severe hypertensive disease complicating pregnancy. 2 Effective reduction in BP was achieved in all but 3 of the 25 patients treated. Careful monitoring of feto-placental function was undertaken to ensure the maintenance of fetal well-being. Maternal and fetal side-effects were minimal and it was not necessary to discontinue the drug in any patient. 3 Labetalol was estimated in the cord blood of the fetus at delivery as well as in the breast milk of mothers on day 3 post partum. There were no adverse effects of the drug on the infants and significant hypotension did not occur. 4 The reults suggest that labetalol has a direct action on fetal lung maturation and this, together with its effective hypotensive effect, contributes to the low perinatal mortality (3.5%) observed. 5 Oculotoxicity due to the labetalol was not observed in the infants delivered. 6 It is concluded that the efficient hypotensive action of labetalol, together with apparent freedom from maternal and fetal side-effects, and consequent improved perinatal mortality, suggest that it is a suitable drug for use in pregnancy complicated by hypertension.

1 In a single blind study seventeen patients with mild or moderate essential hypertension and normal renal function were treated with labetalol alone in increasing doses from 300 via 600 to 1200 mg daily. 2 Average supine BP (systolic/diastolic) was reduced by 24/19 mm Hg. Seven patients attained a diastolic BP less than or equal to Hg. A significant postural fall in systolic BP was recorded, but no symptomatic orthostatic hypotension occurred. 3 In twelve patients measurements of plasma volume (125I-albumin), extracellular volume (82Br-space) and glomerular filtration rate (51Cr-EDTA clearance) on placebo and subsequently labetalol showed no systemic changes. 4 Side effects were few causing two withdrawals because of impotence and arthralgia. 5 It is concluded that monotherapy with labetalol results in clinically relevant, persistent and dose dependent reduction in BP in patients with mild or moderate essential hypertension, apparently without concomitant expansion of body fluid volumes or influence on glomerular filtration rate.

1 Hypertension in West Indians and Africans is common and has an unacceptably high mortality in the younger patients. 2 Fifty-three patients received labetalol (a combined alpha- and beta-adrenoreceptor antagonist) as part of an open evaluation of its anti-hypertensive effect. Ten non-caucasian patients were included. 3 Significant reductions in systolic and diastolic pressures were obtained in the caucasian patients, the African and West Indian patients remaining refractory to therapy.

1. Labetalol, a new drug combining alpha-and beta-adrenoceptor blocking properties, has been compared with placebo in a double-blind crossover study of a group of patients with mild to moderate essential hypertension (blood pressure 150/100 to 189/114 mmHg). 2. Labetalol and propranolol lowered blood pressure satisfactorily in the supine position, but labetalol reduced blood pressure more in the erect posture and following exercise and induced less bradycardia. Thus alpha- as well as beta-adrenoceptor blocking actions appear to contribute to blood pressure reduction. 3. Side effects attributable to labetalol were few. The effective dose ratio labetalol: propranolol was 2.5:1 (w/w). 4. Labetalol, a new form of hypotensive agent, merits further controlled assessment of its usefulness in relation to existing drugs.

1 Labetalol was given to 41 hypertensive patients in a divided dosage of 150--2,400 mg daily for periods ranging from 1--64 months. 2 Monotherapy with labetalol was adequate in 12 out of 19 patients with essential hypertension and in 15 out of the 22 with renal hypertension. 3 Following a single dose of labetalol 200 mg orally a hypotensive response was seen between 1.5 and 2 hours. 4 In the doses used there was no exercise or postural hypotension. 5 No reduction in overall renal function attributable to labetalol was seen.

1 Labetalol reduces blood pressure when given by fast or slow intravenous injection. 2 The extent of the reduction in arterial pressure is independent of the rate of injection but the rate of fall of blood pressure can be controlled by varying the rate of injection. There is little effect on heart rate. 3 These observations suggest that labetalol possesses important advantages over other vasodilator hypotensive drugs in current use.

1 Diazoxide 300 mg and labetalol 150 mg were each injected intravenously on separate occasions into five patients with essentail hypertension. The reduction in BP caused by labetalol was slightly greater than that produced by diazoxide. 2 In contrast the reduction in cerebral blood flow (CBF) by labetalol was not statistically significant, whereas diazoxide gave a greater and statistically significant reduction in CBF. 3 These observations suggest that labetalol may have an advantage over diazoxide for the rapid reduction in BP.

1 The effect of labetalol has been assessed in an open clinical trial in 19 patients with sub-optimal control of blood pressure on other therapy, and in a placebo-controlled cross-over study. Most patients were taking a diuretic before the trial and they continued to do so during the trial. 2 In the open trial, labetalol successfully lowered blood pressure in most of the patients. Average daily dose was about 600 mg. The placebo-controlled trial confrimed the anti-hypertensive effect. 3 A clear postural hypotensive effect was seen. A few patients noted postural faintness as a side-effect, especially in a hot environment; but it was not troublesome. 4 There were few other side-effects. One patient experienced an increase in serum glumatic--oxalic transaminase (SGOT) and another an increasing anti-nuclear factor titre, but it is not yet certain that these were due to labetalol.

1 Labetalol, an alpha- and beta- adrenoceptor blocking drug, was compared with acebutolol, alone or associated with dihydralazine in forty patients with moderate essential hypertension. 2 Labetalol (400--800 mg daily) seemed to have a slightly higher potency than acebutolol alone (400--800 mg daily). 3 Labetalol (1200--1600 mg daily) had the same potency as the combination of acebutolol (400--800 mg daily) and dihydralazine (50--100 mg daily). 4 Contrarily to acebutolol, the drop in blood pressure with labetalol was not correlated with initial plasma renin activity. 5 Labetalol side effects were minor and did not lead to drug withdrawal.

1 Labetalol, a beta- and alpha-adrenoreceptor-blocking drug, has been used in the treatment of hypertension in a total of 32 patients for over 4.5 yr, 14 patients for 3 yr or more. 2 Labetalol seems to have a similarly potency of methyldopa and the adrenergic neurone-blocking drugs. 3 Postural hypotension was only observed at doses over 2 g/d. It was the reason for stopping treatment in two patients. 4 Dosage varied; average 889 mg/d, range 75-3,200 mg. Tolerance did not develop. 5 Side-effects led to drug withdrawal in four patients

1 Patients with combined hypertension and angina pectoris may represent a therapeutic dilemma, with the angina being refractory to conventional beta-blockade. 2 The added benefit of peripheral vasodilation in control of blood pressure is documented in the case of nifedipine. 3 Improved blood pressure control by added nifedipine may not be accompanied by decreased severity of angina pectoris, emphasizing the complex causation of the angina in such patients. 4 The clinically proven added alpha-blocking activity of labetalol distinguishes labetalol from other beta-blockers. However, the suggested benefits of the added alpha-activity in patients with hypertension and angina remain to be proven by further trials in patients.

1 The results of the treatment of 8573 hypertensive patients with labetalol in general practice, for periods between 1 month and 5 yr, are reviewed. 2 The data reviewed were obtained from the published literature together with our own published (Kane et al., 1976; Kane et al., 1979) and more recent (unpublished) work. 3 Between 60% and 80% of severe (diastolic blood pressure greater than 120 mmHg) and previously uncontrolled hypertensives responded satisfactorily to the drug, as did up to 88% of mild to moderate hypertensives. 4 The anti-hypertensive effect of labetalol was not dependent on the frequency of administration, twice and three times daily treatment regimes being equally effective. 5 The withdrawal rate attributable to side-effects was between 6% and 13%. Tiredness, dizziness, headache and upper gastro-intestinal symptoms were the four principal side-effects, but they were usually transient when labetalol treatment was continued. 6 No drug interactions or adverse haematological or biochemical changes were seen.

1 A new anti-hypertensive agent (labetalol) with alpha- and beta-adrenoreceptor-blocking properties has been assessed in 30 patients in a general practice. 2 Significant reduction in blood pressure and pulse rate occurred at a dose of 400 mg/d. A further significant reduction in blood pressure but not of pulse rate occurred at a dose of 800 mg/d. 3 After 4 weeks' treatment on the higher dose the mean fall in systolic and diastolic pressures compared with the pre-trial pressures was 36 and 24 mmHg, respectively. Side-effects were generally mild.

1 In a multicentre open trial, labetalol was given to 128 patients in ten centres. Forty-three patients had not previously received antihypertensive therapy; the remainder (85 patients) had been on antihypertensive therapy with either unsatisfactory BP control or troublesome side-effects. 2 Thirty-two patients were withdrawn from the trial in the first 6 months of therapy, 24 (19% of the total) because of side-effects. 3 Control of BP was generally satisfactory or considerably improved. Other drugs (usually a diuretic) had to be added in 23 patients. 4 There was an abnormality of liver function in one patient; otherwise there were no biochemical or haematological problems.

1 Eighty-five women with severe hypertension complicating pregnancy were treated with oral labetalol (Trandate). Six of these had a twin pregnancy and 54 had proteinuria. 2 Effective control of the blood pressure was achieved in all but six patients. The maximum dose of labetalol prescribed was 1200 mg daily. There were no significant maternal or foetal side-effects. 3 Foeto-placental function was carefully monitored in all patients. Twenty-four of the 89 infants born alive showed evidence of intra-uterine growth retardation, the highest incidence occurring in the group of patients with essential hypertension complicated by pregnancy induced hypertension. 4 The low perinatal mortality of 4.4% was a reflection of the meticulous control of the blood pressure. 5 There were no congenital malformations or evidence of oculotoxicity in any of the infants delivered. 6 The efficient hypotensive action of orally administered labetalol together with the absence of maternal and foetal side effects and consequent improved perinatal mortality confirms that it is an eminently suitable drug for the treatment of hypertension complicating pregnancy.

The effects of single oral doses of indoramin (mean dose 58 mg), abetalol (mean dose 150 mg), alinidine 80 mg and placebo on arterial pressure and heart rate in the supine and standing positions were studied in six normal volunteers. Doses were chosen to give equivalent reductions of arterial pressure in the standing position. Observations were made before and at 2 and 4 h after drug administration. Plasma noradrenaline (NA) was measured at each time interval in the supine position, and after 4 min of standing. Plasma renin activity (PRA) was measured at each time interval after 30 min in the standing position. In the supine position, alinidine produced a significant reduction of systolic arterial pressure from 124.0 +/- 3.0 mm Hg to 104.3 +/- 4.1 mm Hg at 2 h (P less than 0.01) and to 101.7 +/- 2.2 mm Hg at 4 h (P less than 0.01). Diastolic pressure was reduced from 74.7 +/- 2.6 mm Hg to 57.0 +/- 4.6 mm Hg at 4 h (P less than 0.01). Arterial pressure was unchanged after indoramin or labetalol administration. In the supine position, heart rate was unchanged after indoramin, and small reductions were observed after labetalol and alinidine. Indoramin produced a significant increase in plasma NA. A small increase of plasma NA was observed after labetalol, and a small decrease after alinidine. In the standing position, the three active drugs reduced systolic arterial pressure to a similar extent (indoramin, -26.7 mm Hg at 4 h after drug administration; labetalol, -21.3 mm Hg at 2 h; alinidine, -21.7 mm Hg at 4 h).(ABSTRACT TRUNCATED AT 250 WORDS)

1 Labetalol has been compared with propranolol in a double-blind, double-dummy study of 24 patients with mild or moderate essential hypertension. 2 Two patients were unable to tolerate propranolol and five labetalol, because of symptom side effects; this difference was not significant (P greater than 0.1). 3 On a self-administered questionnaire, labetalol was associated with a greater number of side effects per patient than propranolol, but no individual side effect was significantly more common with either drug. 4 There was no difference in the number of spontaneously reported side effects between the two drugs. 5 Both drugs impaired pulmonary function, but propranolol caused a greater reduction than labetalol after 8 weeks of treatment. 6 We conclude that labetalol and propranolol are similarly effective and acceptable to the patient.

1 Forty-one patients with mild to moderate hypertension have been treated with labetalol for up to 5 years. 2 Mean BP before treatment was 180/107 mm Hg, after 2--3 yr treatment was 136/81 mmHg and after 5 yr was 136/74 mmHg. 3 One patient developed a licheniform rash and two patients have died of myocardial infarction. No other side-effects, not already observed in a previously reported double-blind trial, have emerged.

1 Labetalol is an effective agent in essential hypertension as documented in open studies and controlled studies in which its efficacy has been compared with both placebo and a variety of other anti-hypertensive drugs. 2 Labetalol given by mouth lowers blood pressure rapidly. There is no evidence of tolerance to its anti-hypertensive action. 3 Adverse effects include excessive hypotension, but only when the drug is given in large doses. Epigastric discomfort and scalp tingling have been documented especially after intravenous administration. 4 From a pharmacokinetic and pharmacodynamic point of view, labetalol can be given once daily, but postural hypotension after large (greater than 1 g) single doses may limit the usefulness of once daily regimes. Twice daily administration appears an acceptable compromise.

1 Seventeen men, aged 45-57 yr, with essential hypertension showed obvious and, in the standing position, dose-related reductions in blood pressure during treatment with oral labetalol with weekly dose increments. 2 Pulse rate changes were not related to dose but reduced compared with pre-treatment values. 3 No postural hypotension was recorded indicating lack of a dominant alpha-adrenoreceptor-blocking component. 4 There was a small increase in mean fasting blood glucose levels during labetalol treatment but no alteration in insulin activity or response to an oral glucose tolerance test.

1 Labetalol, a new hypotensive drug combining alpha- and beta-adrenoreceptor antagonist properties, has been compared with propranolol in the treatment of severe hypertension (blood pressure 190/115-249/139 mmHg) in a double-blind trial lasting 14 weeks. Additional diuretic therapy was given to both groups of patients. 2 Both drugs caused an effective reduction in blood pressure, bbut labetalol caused a greater fall in pressure in the standing position and after exercise. Two groups of nine patients have each completed the trial so far. Group average pressures for the last 3 weeks of treatment were: for labetalol 137/87 supine, 121/84 standing, and 117/78 mmHg after exercise; and for propranolol, 138/87 supine, 132/93 standing, and 133/94 mmHg after exercise. 3 Group average heart rates were lower in all three positions for those patients treated with propranolol compared with labetalol. 4 The average final dose ratio for labetalol: propranolol was 1.44:1 (w/w). 5 Labetalol initially induced a number of side-effects, predominantly related to alpha-adrenoreceptor blockade, which disappeared by the end of the trial. 6 Labetalol, in conjunction with diuretic therapy, was at least as effective as propranolol in lowering blood pressure in patients with severe hypertension.

1Labetalol is a new compound with antagonistic effects at both alpha- and beta-adrenoreceptor sites. 2 When given to 12 hypertensive patients at an average daily dosage of 273 mg for 7 months statistically significant reductions (compared with pretreatment values) in recumbent and standing blood pressure were observed. 3 Treatment has to be withdrawn in one patient because of vivid dreams, and dosage was reduced in one patient because of dizziness. Otherwise no side-effects of importance were noted. 4 It can therefore be concluded that labetalol offers a useful anti-hypertensive effect and that this compound is well tolerated.

1 The efficacy of labetalol in lowering blood pressure has been assessed in a group of 16 patients with severe hypertension whose blood pressure was inadequately controlled (supine diastolic blood pressure greater than 110 mmHg on two consecutive occasions) on existing therapy or in whom severe side-effects necessitated a change in therapy. 2 All patients had an original pretreatment supine diastolic blood pressure of greater than 120 mmHg and most had evidence of target organ damage. Patients were hospitalized for the purposes of changeover of therapy, labetalol being added to the existing regime which was reduced stepwise and eventually withdrawn. 3 Treatment with labetalol resulted in satisfactory blood pressure control in 10 of 16 patients in this study but high doses were required, the mean daily dose being 3,091 mg (range 1,200-8,000). 4 Treatment with discontinued in 6 patients on account of postural hypotension (3), failure to control supine diastolic blood pressure (2) and retention of urine (1). Long-term treatment was relatively free from side-effects. 5 From preliminary studies in animals it is suggested that an action within the central nervous system may contribute to the hypotensive effect of labetalol.

1 In nine hypertensive subjects with angina pectoris, labetalol diminished the incidence of chest pain occurring spontaneously or induced by exercise. 2 Labetalol lowered BP in all subjects. 3 Exercise tolerance at maximum levels was increased by labetalol. 4 Improved cardiac function by labetalol may be related to decreased afterload on the left ventricle, and diminished oxygen utilization by the myocardium.

1 The effects of labetalol, bethanidine and combined treatment with both drugs were compared in a within-patient randomized cross-over study in mild essential hypertension. Attention was directed to whether or not labetalol and bethanidine differed in their pattern of effect on arterial BP and whether evidence of synergism was apparent. 2 At the doses used labetalol significantly lowered systolic and diastolic BPs and heart rate lying, sitting, standing and after exercise. The dose of bethanidine used did not affect heart rate significantly while lowering systolic and diastolic BPs only after exercise and less clearly on standing. Combined treatment lowered BPs on standing and after exercise and heart rate after exercise. 3 The type and frequency of side-effects were similar with bethanidine and labetalol but were much less with combined treatment. 4 No evidence of synergism was observed.