Journal of Human 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 Prichard1, BR Graham1 and JM Cruickshank2 1Centre for Clinical Pharmacology, University College, 5 University Street, London WC1E 6JJ, UK; 242 Harefield, Long Melford, Suffolk CO10 9DE, UK After a slow start, beta-blockers have become widely dial infarction where they are often under used. There used as first-line agents in the treatment of hyperten- is some evidence that even in post-infarction patients sion, and recommended as such in recently published with co-existent chronic obstructive airways disease, guidelines. There is evidence that the beta1-selective usually regarded as a contra-indication, experience an agents are more efficacious than non-selective blockers improved 2-year survival with the use of beta-blockers. that inhibit both beta1 and beta2 receptors. Notwith- Recently they have also been demonstrated to improve standing some earlier evidence to the contrary, it prognosis in heart failure patients, previously regarded appears that beta1-selective drugs are equi-effective in as a contra-indication. Likewise, recent studies have young and elderly whites, younger, ie, under mid 60s, shown that atenolol was at least as effective as captopril blacks. It is with the combination of age and being black in improving the outlook in hypertensive patients with that beta-blockers are usually less useful than some non-insulin dependant diabetes. While earlier compari- other groups of antihypertensive drugs, most notably sons with the non-selective lipid soluble propranolol calcium antagonists and diuretics. Primary prevention indicated otherwise, comparisons with beta1-selective studies indicate beta-blockers reduce the incidence of agents have indicated a similar effect on quality of life cerebro-vascular disease and coronary heart disease in assessments with angiotensin-converting enzyme younger patients but they appear less effective than inhibitors. Journal of Human Hypertension (2000) 14, Suppl diuretics in the elderly. Beta-blockers are particularly 1, S63–S68. indicated in patients who have experienced a myocar- Keywords: beta-blockers; co-existant disease; quality of life Introduction from use as it gave tumours in mice. However, when propranolol was introduced in January 1964 it was During a double-blind trial in angina pectoris with evaluated from the start in hypertension.2–4 the first clinically used beta-blocker, pronethalol, a At first there was considerable resistance to the small fall in blood pressure was noted and the anti- use of beta-blocking drugs in hypertension.5 There hypertensive effect of pronethalol was subsequently was reluctance to using drugs for hypertension that 1 reported (Figure 1). Pronethalol was withdrawn led to a rise in peripheral resistance and a fall in cardiac output. Also, as a relatively low dose of pro- pranolol completely blocked the tachycardia pro- duced by a dose of isoprenaline which previously gave a marked tachycardia, it was considered that the larger doses of propranolol required for hyper- tension treatment might be unsafe, and any clinical effect would not be due to beta-adrenergic blockade. However, a much larger dose of beta-receptor block- ing drug is required to produce a maximum reduction in the heart rate at low levels of sympath- etic activity, as in the standing position. It required persistence to overcome the initial resistance to the use of beta-blockers in the treatment of hyperten- sion. 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 Figure 1 Fall in blood pressure with 4 weeks pronethalol treat- 1965, ‘everything from watermelon seeds to dilute ment compared to 4 weeks of placebo in 12 normotensive angina hydrochloric acid has at one time or another suc- patients. Double-blind study average of 4 weekly readings after cessfully treated hypertension. I hope that proprano- (after Prichard1). lol does not fit into this category.’6 Beta-blockers have become first line treatment for hypertension, 7 Correspondence: Brian NC Prichard, Centre for Clinical Pharma- confirmed recently by the guidelines of JNC VI cology, University College, 5 University Street, London WC1E (Figure 2). They are also useful in combination in 6JJ, UK more resistant cases. Beta-blockers in hypertension BNC Prichard et al S64 Beta1 selectivity How beta-blockers lower the blood pressure still remains unclear, but it does seem to be a property 6,8 of beta1 blockade. As was reported early in the evaluation of beta blockade, adrenaline in the pres- ence of beta2 blockade produces a greater rise of blood pressure because its beta2 vasodilator action, previously partially offsetting its alpha vasoconstric- tor effect, is inhibited.9 It can therefore be postulated that beta2 blockade antagonises the modest back- ground vasodilator effect of circulating adrenaline, and this attenuates the fall in blood pressure from the beta1 block. This could explain the 2–3 mm Hg Figure 2 Algorithm for the treatment of hypertension (after JNC greater fall in blood pressure seen with beta1 block- VI7). ade as opposed to non-selective block. Selective beta2 blockade (ICI 118 551) does not lower the 6 Variation in the pharmacological properties of blood pressure. Our own early studies demonstrated that propran- beta-blocking drugs olol in titrated doses was equally effective to the Beta-blocking drugs differ in various aspects. Pro- then available potent antihypertensive drugs, the pranolol is a non-selective agent blocking both beta1 centrally acting methyldopa, and the adrenergic receptors, eg, at sympathetic innervation of the neurone inhibiting drugs bethanidine and guanethi- heart, and beta2 receptors eg, in bronchial and vas- dine which thus lower the blood pressure by cular smooth muscle, it also has membrane stabilis- inhibiting vasoconstrictor impulses to alpha recep- ing activity or local anaesthetic effects, though this tors.3,10 Recent large clinical trials have demon- property does not contribute to its antihypertensive strated that beta-blockers, atenolol11–14 or acebuto- effect. Propranolol is a pure antagonist, it has no par- lol15 are similar in antihypertensive effect to tial agonist activity, ie, stimulating effect, unlike examples from the major classes of hypotensive agents such as pindolol. Beta-blockers have also drugs. Similarly, in a large survey of veterans’ been developed with other properties (Table 1),6 hypertension clinic the achieved blood pressure such as alpha1 blocking activity, eg, carvedilol, a with beta-blockers was similar to other agents, with non-selective blocker which also has an anti-oxidant or without a diuretic (Table 2).16 Bisoprolol is poss- action, or nebivolol, a beta1-selective agent which ibly the most beta1 selective agent generally avail- has a nitric oxide dependant vasodilator property. able,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 Progress in the use of beta-blockers in 17,19,20 hypertension and associated conditions of hypertension. There has been continuing progress in the field of Combination treatment beta blockade over 35 years, both in terms of phar- macological development and in the wider appreci- Weir21 and Epstein and Bakris22 have recently dis- ation of their clinical application. cussed the value of combination versus single drug regimens in the treatment of hypertension. Frishman 23 Table 1 Classification of beta-adrenoceptor blocking drugs et al reported a large factorial study involving a total of 512 patients where bisoprolol 2.5 mg, 10 mg ␤ ␤ Division I Non-selective ( 1 2 block) Group I ISA Membrane eg, Alprenolol, Table 2 Veterans survey hypertension clinics active Oxprenolol Group II — Membrane eg, Propranolol active No. BP level (mm Hg) Group III ISA — eg, Pindolol, Carteolol Group IV — — eg Timolol, Nadolol, One drug regimens Sotalol (+ class III) Diuretic 872 140.8/81.8 Beta-blocker 299 141.2/84.3 ␤ Division II 1-selective ACE inhibitor 489 142.2/85.9 Group I ISA Membrane eg, Acebutolol Calcium antagonist 799 149.0/86.5 active Other: one drug 267 144.7/83.8 Group III ISA — eg, Practolol, Celiprolol Group IV — — eg, Atenolol, Betaxolol, Diuretic Plus Bisoprolol, Metoprolol Beta-blocker 390 140.1/83.4 Sympatholytic 289 142.1/83.5 Division III Non-selective block and peripheral vasodilator ACE inhibitor 394 142.7/85.0 ␣ Block eg, Labetalol, Carvedilol Calcium antagonist 460 146.3/85.3 Other drug 140 146.4/84.6 Division IV Selective + peripheral vasodilator NO dependent eg, Nebivolol Total all patients 6100 144.2/84.7 vasodilation (After Perry et al.16) Journal of Human Hypertension Beta-blockers in hypertension BNC Prichard et al S65 or 40 mg, hydrochlorothiazide 6.25 mg or 25 mg, and placebo were given in all possible combi- nations. 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 biso- prolol 5 mg and 6.25 mg hydrochlorothiazide was shown,24 while Prisant et al25 found the combi- nation with low dose hydrochlorothiazide con- trolled blood pressure to a similar extent to amlodip- ine, but both drugs were more efficacious than enalapril. Effect of age and race on the antihypertensive effect of beta-blockers in hypertension Figure 3 Percentage reduction in risk of death over 2 years beta blockade post-infarction according to systolic blood pressure It has been suggested in the past that the response (after Gottlieb et al31). of blood pressure to beta blocking drugs in the eld- erly and blacks was poor, although much of the experience which led to this opinion was based on Ischaemic heart disease non-selective agents.6 Beta-blockers are effective agents for the treatment Frishman et al24 compared bisoprolol, hydrochlor- of angina and are well established for secondary pre- othiazide and the combination.