New approaches to the uses of beta blocking drugs in hypertension

(2000) 14, Suppl 1, S63 S68 2000 Macmillan Publishers Ltd All rights reserved 0950-9240/00 $15.00 www.nature.com/jhh New approaches to the uses of beta blocking drugs in hypertension BNC Prichard 1, BR Graham 1 and JM Cruickshank 2 1 Centre for Clinical Pharmacology, University College, 5 University Street, London WC1E 6JJ, UK; 2 42 Harefield, Long Melford, Suffolk CO10 9DE, UK After a slow start, beta-blockers have become widely used as first-line agents in the treatment of hypertension, and recommended as such in recently published guidelines. There is evidence that the beta 1 -selective agents are more efficacious than non-selective blockers that inhibit both beta 1 and beta 2 receptors. Notwithstanding some earlier evidence to the contrary, it appears that beta 1 -selective drugs are equi-effective in young and elderly whites, younger, ie, under mid 60s, blacks. It is with the combination of age and being black that beta-blockers are usually less useful than some other groups of antihypertensive drugs, most notably calcium antagonists and diuretics. Primary prevention studies indicate beta-blockers reduce the incidence of cerebro-vascular disease and coronary heart disease in younger patients but they appear less effective than diuretics in the elderly. Beta-blockers are particularly indicated in patients who have experienced a myocar- dial infarction where they are often under used. There is some evidence that even in post-infarction patients with co-existent chronic obstructive airways disease, usually regarded as a contra-indication, experience an improved 2-year survival with the use of beta-blockers. Recently they have also been demonstrated to improve prognosis in heart failure patients, previously regarded as a contra-indication. Likewise, recent studies have shown that atenolol was at least as effective as captopril in improving the outlook in hypertensive patients with non-insulin dependant diabetes. While earlier comparisons with the non-selective lipid soluble propranolol indicated otherwise, comparisons with beta 1 -selective agents have indicated a similar effect on quality of life assessments with angiotensin-converting enzyme inhibitors. (2000) 14, Suppl 1, S63 S68. Keywords: beta-blockers; co-existant disease; quality of life Introduction During a double-blind trial in angina pectoris with the first clinically used beta-blocker, pronethalol, a small fall in blood pressure was noted and the antihypertensive effect of pronethalol was subsequently reported (Figure 1). 1 Pronethalol was withdrawn Figure 1 Fall in blood pressure with 4 weeks pronethalol treatment compared to 4 weeks of placebo in 12 normotensive angina patients. Double-blind study average of 4 weekly readings after (after Prichard 1 ). Correspondence: Brian NC Prichard, Centre for Clinical Pharmacology, University College, 5 University Street, London WC1E 6JJ, UK from use as it gave tumours in mice. However, when propranolol was introduced in January 1964 it was evaluated from the start in hypertension. 2 4 At first there was considerable resistance to the use of beta-blocking drugs in hypertension. 5 There was reluctance to using drugs for hypertension that led to a rise in peripheral resistance and a fall in cardiac output. Also, as a relatively low dose of propranolol completely blocked the tachycardia produced by a dose of isoprenaline which previously gave a marked tachycardia, it was considered that the larger doses of propranolol required for hypertension treatment might be unsafe, and any clinical effect would not be due to beta-adrenergic blockade. However, a much larger dose of beta-receptor blocking drug is required to produce a maximum reduction in the heart rate at low levels of sympathetic activity, as in the standing position. It required persistence to overcome the initial resistance to the use of beta-blockers in the treatment of hypertension. We have come a long way since Ahlquist, in 1967, was reported to have remarked at the end of the first symposium on beta-blockers in October 1965, everything from watermelon seeds to dilute hydrochloric acid has at one time or another successfully treated hypertension. I hope that propranolol does not fit into this category. 6 Beta-blockers have become first line treatment for hypertension, confirmed recently by the guidelines of JNC VI 7 (Figure 2). They are also useful in combination in more resistant cases.

S64 Beta-blockers in hypertension Figure 2 Algorithm for the treatment of hypertension (after JNC VI 7 ). Variation in the pharmacological properties of beta-blocking drugs Beta-blocking drugs differ in various aspects. Propranolol is a non-selective agent blocking both beta 1 receptors, eg, at sympathetic innervation of the heart, and beta 2 receptors eg, in bronchial and vascular smooth muscle, it also has membrane stabilising activity or local anaesthetic effects, though this property does not contribute to its antihypertensive effect. Propranolol is a pure antagonist, it has no partial agonist activity, ie, stimulating effect, unlike agents such as pindolol. Beta-blockers have also been developed with other properties (Table 1), 6 such as alpha 1 blocking activity, eg, carvedilol, a non-selective blocker which also has an anti-oxidant action, or nebivolol, a beta 1 -selective agent which has a nitric oxide dependant vasodilator property. Progress in the use of beta-blockers in hypertension and associated conditions There has been continuing progress in the field of beta blockade over 35 years, both in terms of pharmacological development and in the wider appreciation of their clinical application. Table 1 Classification of beta-adrenoceptor blocking drugs Division I Non-selective ( 1 2 block) Group I ISA Membrane eg, Alprenolol, active Oxprenolol Group II Membrane eg, Propranolol active Group III ISA eg, Pindolol, Carteolol Group IV eg Timolol, Nadolol, Sotalol (+ class III) Division II 1 -selective Group I ISA Membrane eg, Acebutolol active Group III ISA eg, Practolol, Celiprolol Group IV eg, Atenolol, Betaxolol, Bisoprolol, Metoprolol Division III Block Non-selective block and peripheral vasodilator eg, Labetalol, Carvedilol Division IV Selective + peripheral vasodilator NO dependent eg, Nebivolol vasodilation Beta 1 selectivity How beta-blockers lower the blood pressure still remains unclear, but it does seem to be a property of beta 1 blockade. 6,8 As was reported early in the evaluation of beta blockade, adrenaline in the presence of beta 2 blockade produces a greater rise of blood pressure because its beta 2 vasodilator action, previously partially offsetting its alpha vasoconstrictor effect, is inhibited. 9 It can therefore be postulated that beta 2 blockade antagonises the modest background vasodilator effect of circulating adrenaline, and this attenuates the fall in blood pressure from the beta 1 block. This could explain the 2 3 mm Hg greater fall in blood pressure seen with beta 1 blockade as opposed to non-selective block. Selective beta 2 blockade (ICI 118 551) does not lower the blood pressure. 6 Our own early studies demonstrated that propranolol in titrated doses was equally effective to the then available potent antihypertensive drugs, the centrally acting methyldopa, and the adrenergic neurone inhibiting drugs bethanidine and guanethidine which thus lower the blood pressure by inhibiting vasoconstrictor impulses to alpha receptors. 3,10 Recent large clinical trials have demonstrated that beta-blockers, atenolol 11 14 or acebutolol 15 are similar in antihypertensive effect to examples from the major classes of hypotensive drugs. Similarly, in a large survey of veterans hypertension clinic the achieved blood pressure with beta-blockers was similar to other agents, with or without a diuretic (Table 2). 16 Bisoprolol is possibly the most beta 1 selective agent generally available, 17 as has been confirmed by recent receptor binding studies. 18 There is some evidence that it may be more effective than atenolol in the control of hypertension. 17,19,20 Combination treatment Weir 21 and Epstein and Bakris 22 have recently discussed the value of combination versus single drug regimens in the treatment of hypertension. Frishman et al 23 reported a large factorial study involving a total of 512 patients where bisoprolol 2.5 mg, 10 mg Table 2 Veterans survey hypertension clinics No. BP level (mm Hg) One drug regimens Diuretic 872 140.8/81.8 Beta-blocker 299 141.2/84.3 ACE inhibitor 489 142.2/85.9 Calcium antagonist 799 149.0/86.5 Other: one drug 267 144.7/83.8 Diuretic Plus Beta-blocker 390 140.1/83.4 Sympatholytic 289 142.1/83.5 ACE inhibitor 394 142.7/85.0 Calcium antagonist 460 146.3/85.3 Other drug 140 146.4/84.6 Total all patients 6100 144.2/84.7 (After Perry et al. 16 )

Beta-blockers in hypertension or 40 mg, hydrochlorothiazide 6.25 mg or 25 mg, and placebo were given in all possible combinations. The low dose combination of bisoprolol 2.5 mg and hydrochlorothiazide 6.25 mg lowered blood pressure to less than 70 mm Hg diastolic in 61% of patients. In a further study the value of bisoprolol 5 mg and 6.25 mg hydrochlorothiazide was shown, 24 while Prisant et al 25 found the combination with low dose hydrochlorothiazide controlled blood pressure to a similar extent to amlodipine, but both drugs were more efficacious than enalapril. S65 Effect of age and race on the antihypertensive effect of beta-blockers in hypertension It has been suggested in the past that the response of blood pressure to beta blocking drugs in the elderly and blacks was poor, although much of the experience which led to this opinion was based on non-selective agents. 6 Frishman et al 24 compared bisoprolol, hydrochlorothiazide and the combination. There was no reduction in the fall of blood pressure in those patients over 60 years compared to those below that age with bisoprolol alone or in combination. Materson et al 11 13 in their double-blind parallel group study of six different antihypertensive regimens did not find any age-related response to atenolol in white patients, 72% or those over 60 years old were successfully controlled compared to 65% below 60 years old. Jamerson and DeQuattro 26 reviewed 13 clinical trials in African Americans published between 1988 and 1993, and noted less fall of blood pressure with ACE inhibitors and beta-blockers compared to calcium channel blockers and diuretics. Materson et al 11 13 reported that black patients under 60 showed a 51% response rate to atenolol, second only to diltiazem, whereas, while 45% of atenolol patients responded in the over 60s blacks, better responses were obtained with diltiazem 85%, hydrochlorothiazide 64%, clonidine 58% and prazosin 49%. Primary prevention in hypertension Several retrospective studies have suggested that the incidence of fatal and non-fatal heart disease is reduced by beta blockade. 27 A number of prospective trials have demonstrated that diuretics and beta-blockers reduce the development of complications of hypertension, most clearly seen with stroke and heart failure, less clear with coronary heart disease. 27,28 However, in the elderly diuretics appeared superior to beta-blockers in primary prevention in hypertension for both coronary events and cerebrovascular accidents. 29,30 Co-existent disease Recently acquired evidence in important areas is dictating that new approaches should be made to the use of beta-blockers in patients with co-existent disease, which previously had been regarded as relative contraindications to the use of beta-blockers. Figure 3 Percentage reduction in risk of death over 2 years beta blockade post-infarction according to systolic blood pressure (after Gottlieb et al 31 ). Ischaemic heart disease Beta-blockers are effective agents for the treatment of angina and are well established for secondary prevention after myocardial infarction by numerous studies. 6 There is evidence that not all beta-blockers are equi-effective, the presence of significant partial agonist activity (or intrinsic sympathomimetic action (ISA)) renders them less effective. Sotolol, with its additional anti-arrhythmic class III action, also should not be used for secondary prevention after myocardial infarction. Gottlieb et al 31 recently published a survey of post-infarction beta blockade usage in 201 752 patients. They found that benefit was seen regardless of systolic blood pressure (Figure 3), age (Figure 4) or ejection fraction (Figure 5), and in patients with COPD, widely regarded as a contraindication to beta blockade, there was also a reduction in the risk of death 2 years post-infarction (Figure 6). Heart failure Heart failure used to be regarded as an important contraindication to beta blockade, 6 we in fact reported the first case of heart failure precipitated by beta blockade as propranolol interfered with the patients compensatory tachycardia for the failing pump. 2 Figure 4 Percentage reduction in risk of death over 2 years beta blockade post-infarction according to age (after Gottlieb et al 31 ).

Beta-blockers in hypertension S66 tality, it was 17.3% on placebo, 11.8% on bisoprolol, a hazard ratio of 0.66 (CI 0.54 0.81, P 0.0001), with sudden deaths 6.3 and 3.6% respectively (ratio 0.56 (CI 0.39 0.80, P = 0.0011). The co-existence of heart failure with hypertension is now an indication for the use of beta blockade, although it would be recommended to first control the blood pressure by other means, as has been our practice for many years. 3 The study of Gottlieb et al, 31 as reported above, found beta-blockers improve prognosis in post-infarction patients with blood pressures over 140 mm Hg, with reduced ejection fractions, although how many had both features is not stated. Figure 5 Percentage reduction in risk of death over 2 years beta blockade post-infarction according to ejection fraction (after Gottlieb et al 31 ). Figure 6 Percentage reduction in risk of death over 2 years beta blockade post-infarction according to COPD (after Gottlieb et al 31 ). However, provided initial doses are very small and dose is titrated carefully beta blockade improves prognosis in patients with heart failure even when added to a regimen including diuretics and ACE inhibitors. Lechat et al 32 recently reported a meta-analysis of studies of beta blockade in heart failure (Table 3). Subsequently the CIBIS II 33 trial has reported and thus there is better evidence of the value of beta 1 selective agents. Bisoprolol reduced all-cause mor- Table 3 Beta blockade in heart failure End-points No. of Odds 95% CI P trials ratio Mortality All trials 16 0.68 0.53, 0.88 0.003 Selective agents 7 0.84 0.61, 1.16 0.30 Non-selective agents 11 0.51 0.34, 0.75 0.001 Hospitalisation for congestive heart failure All trials 18 0.59 0.48, 0.74 0.001 Selective agents 7 0.58 0.43, 0.77 0.001 Non-selective agents 11 0.62 0.44, 0.87 0.006 (After Lechat et al 32 ). Diabetes The co-existent occurrence of diabetes with hypertension has been considered as a relative contraindication for beta blockade. 6 Cruickshank 34 has recently summarised the reasons for this (Table 4). However, recently a number of studies have reported that morality and re-infarction rates. in survivors of myocardial infarction who were also diabetic benefit from beta blockade, at least to a similar degree as non-diabetics. 35,36 Another matter of importance in the day-to-day control of diabetes is the incidence of hypo-glycaemic episodes. Shorr et al 37 found that although numbers were small the risk of hypoglycaemic episodes in hypertensive diabetics treated with beta 1 -selective agents (488 patient years) was not more than with angiotensinconverting enzyme (ACE) inhibitors (1009 patient years), calcium channel blockers (1505 patient years) or thiazides (5098 patient years). Two recent UKPDS studies in diabetic hypertensive patients have been very informative. It was shown that tight control of the blood pressure with atenolol or captopril aiming for less than 150/85 mm Hg, achieving 144/82 mm Hg (n = 758) rather than less tight control with other drugs aiming for less than 180/105 mm Hg, achieving an average of 154/87 mm Hg with 8.4 year follow-up, resulted in a wide range of improved outcomes (Table 5). 38 There was also a 50% reduction in the incidence of heart failure, 34% reduction in worsening retinopathy, 47% reduction in loss of visual activity, and a 29% reduction in the risk of urinary albumin excretion Table 4 Previous negative image of beta-blockers in diabetes 1. A typical beta-blocker tends to increase triglyceride and lower HDL levels. 2. A typical beta-blocker tends to increase fasting blood sugar, HbA1c and insulin resistance. 3. A non-selective beta-blocker can prolong insulin-induced hypoglycaemia and mask hypoglycaemic signs. 4. In the MRC mild hypertension study there was a trend to increase withdrawals on propranolol (vs placebo), due to impaired glucose tolerance. 5. Beta-blockers cause patients to increase weight by 1 2 kg. 6. In the post-myocardial infarction BHAT Study significantly more oral hypoglycaemic agents were required in the propranolol vs placebo, group.

Beta-blockers in hypertension Table 5 Number of patients who attained one or more clinical end-points in aggregates representing specific types of clinical complications, with relative risks comparing tight control of blood pressure with less tight control. S67 Clinical end-point Patients with aggregate end- Absolute risk (events per 1000 P value Relative risk for tight points patient years) control (95% CI) Tight Less tight Tight control Less tight control control control (n = 758) (n = 390) Any diabetes related end-point 259 170 50.9 67.4 0.0046 0.76 (0.62 to 0.92) Deaths related to diabetes 82 62 13.7 20.3 0.019 0.68 (0.49 to 0.94) All cause mortality 134 83 22.4 27.2 0.17 0.82 (0.63 to 1.08) Myocardial infarction 107 69 18.6 23.5 0.13 0.79 (0.59 to 1.07) Stroke 38 34 6.5 11.6 0.013 0.56 (0.35 to 0.89) Peripheral vascular disease 8 8 1.4 2.7 0.17 0.51 (0.19 to 1.37) Microvascular disease 68 54 12.0 19.2 0.0092 0.63 (0.44 to 0.89) (After UKPDS. 38 ) (all with P values better than 0.01). In the companion report light control, BP 143/81 mm Hg, achieved with atenolol 50 or 100 mg o.d. (n = 358) or with captopril 144/83 mm Hg, 25 or 50 mg b.d. (n = 400) was compared. 39 In the seven outcomes tested in Table 5 there was a non-significant trend in favour of atenolol, as was also the case with the incidence of heart failure and sudden death. There was a higher glycated haemoglobin for the first 4 years with atenolol but not for the last 5 years. There was no difference in the incidence of hypoglycaemic problems. Compliance was similar for the first 4 years but then it was 80% for captopril, 74% for atenolol in terms of patient years follow-up (P = 0.0001). This was mainly due to bronchospasm (6%)andclaudicationorcoldfeet(49%)onatenolol, offset to some degree by cough (4%) on captopril. Side effects, quality of life After Croog et al 40 compared propranolol, methyldopa and captopril, the view was held that ACE inhibitors resulted in a better quality of life compared to beta blockade. However, what was later found with the non-selective lipid soluble propranolol did not apply to all beta-blockers. The beta 1 selective atenolol was found to have a similar quality of life score to ACE inhibitors, 41 while the nonselective propranolol was found to have poorer global score, confirming the findings of Croog et al. 40 Further studies confirm that atenolol was similar to captopril, 42 and Fletcher et al 43 in a large doubleblind, randomised parallel group study, observed that cilazapril and atenolol were similar in quality of life assessment, both superior to nifedipine. The highly beta 1 -selective bisoprolol has been reported to be similar to enalapril, 44 while a combination of low dose (6.25 mg) hydrochlorothiazide and bisoprolol was found to have a similar quality of life to amlodipine with a trend to be better than enalapril. 23 A global assessment of the various measures of quality of life in the TOMHS study showed that acebutolol and chlorthalidone were significantly better than placebo, while doxazosin and enalapril did not differ from placebo and amlodipine just failed to reach accepted level of significance. 45 Those beta-blockers such as carvedilol with additional peripheral vaso- dilator action have also been shown to have similar quality of life scores to ACE inhibitors. 46 Conclusion Beta blocking drugs are widely used in the treatment of hypertension and are regarded as first line agents. Particularly beta 1 agents are effective in all major patient groups but less so with elderly black patients. 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