Hypertension 1996 : One Medicine, Two Cultures

The role of beta-blocker therapy in the treatment of arterial hypertension

Fabio Menghini
Department of Cardiology, “S. Eugenio” Hospital, Rome

The fascinating and often contradictory history of beta-blockers begins in 1958, ten years after Ahlquist's receptorial hypothesis, when Powell and Slater described the particular anti-adrenergic properties of a new compound, Dichloroisoproterenol.
Subsequently, with the synthesis (1962) of Propranolol, which earned Sir James Black the Nobel prize for Medicine in 1989, and with the first clinical studies (1964) of the treatment of angina, arterial rhythm and hypertension disorders, this class of drugs left the experimental phase to become part of daily practice.
Despite the thirty-five years that have passed since the introduction of beta-blockers into the therapy of arterial hypertension, some doubts still exist on the exact ways these drugs act on the pressure values.
Various mechanisms have been hypothesised over the years and it is probable that all of these contribute, to varying degrees and under different physiopathological conditions, to determining therapeutic effectiveness.
As is well known, beta-blockers cause a reduction of cardiac inotropism and chronotropism, both at rest and under stress, with the relative reduction of the cardiac rate, the consequent reduction of the pressure rate and subsequent readjustment of the peripheral resistances.
Beta-blockers may also exercise their hypotensive effect through a reduction of renin incretion, a reduction in the release of catecholamine of the synaptic terminals (presynaptic receptorial block), a resetting of the aortic and carotid baroceptors and lastly, through a mechanism of a central modulation type of the sympathetic vasomotor tone.
In the now large family of beta-blockers the various molecules are classified according to different properties of pharmacodynamics and pharmacokinetics, the most important of which for clinical purposes, are cardioselectivlty, intrinsic sympathomimetic activity (ISA) and “metabolic clearance”.

As early as 1967, Lands had identified various models of sensitivity to various sympathomimetic amines, therefore he postulated the existence of two types of beta-receptors: beta 1 receptors, mainly cardiac, and beta 2 receptors, located mainly at the vascular and bronchial level.
At present we have at our disposal cardioselective beta-blockers (the affinity of which, moreover, is dependent on the dosage), non-selective, and molecules with alpha and beta-blocker properties.
A further distinction must be made according to whether ISA is present or not, that is, the property thanks to which the drug, occupying the receptorial site, provokes its partial activation.

*ISA: Intrinsic Sympathomimetic Activity

Beta-blockers are widely used in the treatment of Arterial Hypertension. From the numerous studies of populations carried out, it emerges that these drugs, in monotherapy, allow a good check to be kept on pressure values in approximately 60% of patients with slight or moderate Hypertension, appearing well tolerated in about 85% of cases
At the present time, beta-blocker therapy is to be considered elective in hypertensive patients with:

1. coronary disease (angina pectoris, post-infarct);

2. ventricular and supraventricular tachyarrhythmia;

3. hypertiroidism and more generally in all those conditions where hypertension is the expression of a hyperkinetic condition.

Lipophilic beta-blockers have also proven useful in the treatment of a number of particular neurological syndromes such as hemicrania, essential tremor, cluster headache, at times concomitant with hypertension.
Bearing in mind the importance and ubiquity of the adrenergic system in the control and in the homeostasis of the different organs and systems, makes it easier to approach the topic of relative and absolute contraindications to the use of these drugs and the great variety of side effects that the therapy may induce.
Beta-blockers, by increasing the resistance of the respiratory tract, may precipitate bronchial spasm in patients with a history of asthma and in general should not be administered where there exists a chronic obstructive bronchopathy.
In peripheral arteriopathies, due to the increase in vasoconstrictor tone mediated by the alpha receptors, the beta-blockers may exacerbate the symptomatology and for this reason should be avoided.
Similarly beta-blockers should not be used in patients with pronounced bradycardia and/or disorders of cardiac excito conduction.
In Hypertensive Cardiopathy with a dilatory evolution, beta-blockers may be used, with caution, in small incremental doses but always under conditions of circulation compensation and in association with diuretics and ACE-inhibitors.
There are now numerous references in literature, which suggest a favourable result of this therapeutic approach on the expectation and quality of life.
This benefit seems to be mediated by the capacity of the beta-blocker to restore sensitivity and density of the adergenic beta-receptors, which are believed to progressively and critically reduce in number in the most serious forms of cardiac failure (down-regulation).
Equal caution must be used in treating patients with Insulin-Dependent Diabetes. The beta-blocker may in fact conceal symptoms of hypoglycaemia, worsening and prolonging this condition by blocking glycogenolysis and the release of glucagon. Furthermore, the beta-blockers may worsen the tolerance to glucose in patients with NIDDM through a reduction in the incretion of insulin at pancreatic level. Beta-blockers may have a negative influence on the lipidic profile, reducing the HDL/Total Cholesterol ratio and increasing Triglycerides. This effect does not seem notable when using molecules with ISA and implementing a correct dietetic prescription at the same time.
The side effects on the central nervous system, more frequent as is natural, for molecules with greater lipophilia, include, depression, sleet disorders and reduction of libido.
It is worthwhile recalling that this last disorder, which is given a fair amount of emphasis in the collective medical imagination, is described in various case histories in percentages varying between 1% and 10% of the patients treated.
Perhaps the most frequent (20%) of the side effects of beta blocking therapy is the appearance of asthenia and a proneness to muscular exhaustion. The nature of this disorder is not unambiguous and can be explained by the concomitance of effects at a central cardiac, respiratory and vascular level. The clinical effectiveness of the various molecules appears to be substantially superimposable. As already mentioned, once the decision to follow this therapeutic direction has been taken, the choice of the most suitable drug must be made, bearing in mind the accessory properties described above.
Cardioselective beta-blockers are indicated in the presence of alterations of the glucidic and lipidic metabolism, and where a therapeutic attempt may be correctly hypothesised, in some sub-clinical forms of peripheral arteriopathy and pulmonary pathology.
Beta-blockers with ISA, which are also advisable in oases of cases of carbohydrate intolerance and/or hyperlipoproteinemia, are to be preferred in elderly patients, in subjects carrying out a large amount of physical activity and in those cases where a limited negative chronotropic effect is advisable.
Naturally, the presence of renal or hepatic insufficiency must suggest the use of drugs eliminated by the alternative pathway.
But, after this brief survey of elective indications, relative and absolute contraindications and side effects, we must go into the assigned subject in detail, trying to outline what is, today, the exact role of beta-blockers in the treatment of arterial hypertension.
The subject is very complex and for a correct introduction, a number of preliminary considerations are required:

1. the large-scale trials of primary prevention in the 1980s tested, for reasons that we could define as “registration”, beta-blockers and diuretics. For this reason, what we know today about the capacity of hypotensive therapy to reduce total mortality and cerebral and cardiovascular events refers essentially to these classes of drugs.
2. The reduction of the incidence of strokes in clinical studies has been equal to the estimates on an epidemiological basis. The reduction of coronary events observed in the trials, whilst significant, was approximately one-third less than estimated.
3. The benefit given by hypotensive therapy emerges, although with necessary distinctions, substantially proven for all classes of disease and for all the subgroups of patients.
4. Some data of meta-analysis would suggest a certain superiority of beta-blockers over diuretics in terms of clinical effectiveness.

From these reasoning taken as a whole, there would appear to merge a role for beta-blockers (and for diuretics) as absolute protagonist on the scene of anti-hypertensive treatment.
And these are in fact the current guidelines of the United States’ Joint National Committee which also take into account a cost/benefit criterion which is by all means favourable for these classes of drugs.
These guidelines have not been subsequently agreed with by the Joint Committee of the International Society of Arterial Hypertension and the World Health Organization, which has put all the drugs currently used in the first stage of hypotensive therapy at the same level, based on the following reasons:

1. The benefit shown by clinical studies appears to be more connected to the reduction of pressure values than to the type of drug, also bearing in mind that in several of these studies, in the end many patients took various associations of therapies.
2. The new hypotensive drugs, and in particular ACE-inhibitors and calcium antagonists, present, compared to beta-blockers, a better profile of tolerability, handling and spectrum of use, a substantial metabolic neutrality and above all greater effectiveness in the prevention of damage to the organ. The structural and functional alterations, at the cardiac, vascular and renal levels, are “per se” strongly predictive of subsequent events and the fact of being able to rely on drugs which are intrinsically active in this context provides valid prospects in the prevention of that proportion of cardiac events which more conventional therapy would not be capable of averting.

It appears obvious that this controversy may be solved only when data on events from the several trials currently under way with ACE inhibitors, calcium antagonists and alphalytics, begin to reach maturity.
In the meantime, trying to maintain a correct but difficult equidistant between the fundamentalism of trialistic religion and the “hidden persuasions” of the big pharmaceutical brother, it will be an elementary rule of common sense to act in such a way in the attempt to match the peculiarities of the individual clinical cases to the variety of possible therapeutical options as far as possible.
Moreover, it is the opinion of the writer that, in treating arterial hypertension pharmacologically, the beta-blocker hypothesis must be the first to be examined and, where necessary, to be excluded, especially in the case of a young male patient, who is a non-smoker and with a history or family history of ischaemic cardiopathy.

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Edited by Aldo Campana,