Essential hypertension: pharmacological associations in antihypertensive therapy

By Cristiano Antonino On Dec 8, 2022

In the therapy of essential hypertension, the physician has at his disposal five classes of drugs with different mechanisms of action

Diuretics, beta-blockers, calcium channel blockers, ACE inhibitors and alpha-1-blockers are all considered by the WHO to be drugs of first choice in the treatment of mild IAE (1).

These drugs, which are well known to the practising physician and specialist, have recently been joined by angiotensin II AT1-receptor antagonists, the progenitor of which is losartan.

Essential hypertension, all drugs are characterised by a high profile of therapeutic manageability and tolerability

Furthermore, the existence for each of these pharmacological classes of long-acting molecules or sustained-release pharmaceutical preparations, making single-dose administration possible, facilitates the hypertensive patient’s compliance.

To these general properties must be added the cardioprotection, which these drugs exert in terms of reducing cardiovascular mortality and morbidity or at least regression of left ventricular and arterial hypertrophy.

In 50-60% of patients with mild to moderate IAE, monotherapy, i.e. the use of a single drug from the above-mentioned classes, is sufficient to normalise or sufficiently reduce blood pressure.

In the remaining patients, or when greater antihypertensive efficacy is desired in those in whom normalisation of blood pressure values has not been achieved, pharmacological combination therapy is required in addition to the obvious implementation of non-drug therapeutic measures of a hygienic-dietetic nature.

On the other hand, possible alternatives to combination therapy do not appear to be feasible, since:

1) with current drugs, increasing the average dose of the drug chosen as monotherapy offers a small increase in efficacy in the face of the appearance or worsening of side effects;

2) sequential monotherapy, consisting of replacing one monotherapy with another of a different pharmacological class until the maximum antihypertensive response is obtained, requires long intervention times with the consequent repercussions on therapeutic compliance and trust in the treating physician. Moreover, it seems logical that a disease with a multifactorial pathogenesis such as IAE requires the combination of drugs with different mechanisms of action (2).

The aforementioned characteristics of manageability and tolerability of first-choice drugs, together with their different and often complementary mechanism of action and the possibility of single-dose administration, make it easier than in the past for physicians to manage combination therapy.

It is, in fact, virtually possible to combine 2 or 3 drugs of different classes ad libitum, although, as we shall see, certain pharmacological associations are more recommended than others and some are frankly inadvisable due to the accumulation of possible side effects.

Antihypertensive pharmacological associations are conditioned in part by the cardiovascular pathologies that may be present in the hypertensive patient

For example, if ischaemic heart disease is present, beta-blockers together with dihydropyridines are a logical association, just as diuretics and ACE inhibitors are in the presence of left ventricular failure.

The first step in the antihypertensive pharmacological combination is to add to the monotherapy that has achieved some efficacy a second drug with a different and possibly complementary mechanism of action.

If therapy has been started with a thiazide diuretic (hydrochlorothiazide or chlorthalidone 12.5-25 mg/day), a beta-blocker (preferably beta-1-selective: acebutolol 200-400 mg/day, atenolol 50-100 mg/day, bisoprolol 5-10 mg/day, metoprolol retard 100-200 mg/day) or a long-acting ACE inhibitor (lisinopril 20 mg/day, perindopril 4 mg/day, trandolapril 2 mg/day).

If the ‘first-line’ therapy is a beta-blocker, a thiazide diuretic or a dihydropyridine calcium-channel blocker (amlodipine 5-10 mg/day, felodipine ER 5-10 mg/day, lacidipine 4-8 mg/day, nifedipine GITS 30-60 mg/day) may be added.

If a dihydropyridine or non-dihydropyridine calcium-channel blocker with a negative chronotropic effect (diltiazem retard 300 mg/day, verapamil SR 120-240 mg/day) is to be combined with a second drug, a long-acting ACE-inhibitor should be the preferred choice.

Essential hypertension, beta-blockers can obviously only be combined with dihydropyridines

If a long-acting ACE-inhibitor does not have sufficient antihypertensive efficacy, the best pharmacological combination is a thiazide, a dihydropyridine or a non-dihydropyridine calcium channel blocker.

If long-acting alpha-1-blockers are the initial monotherapy, the combination with any drug from the previous classes, however pharmacologically possible, must take into account their widely varying dosages (doxazosin 2-16 mg/day, terazosin 1-20 mg/day) so as not to enhance their tendency to cause postural hypotension.

As already mentioned, a pharmacological association not recommended is that between beta-blockers and verapamil or diltiazem because of the dangerous additive effect on heart rate and atrio-ventricular and intraventricular conduction times.

Other associations that are not recommended due to the partial overlapping of the mechanisms of action, but in any case not dangerous, are those between calcium channel blockers and diuretics and between beta-blockers and ACE inhibitors.

However, these partial biases are dropped when one encounters a form of hypertension that is resistant to the combination of 2 drugs (3).

In this case, it will be necessary to use 3 or even 4 drugs belonging to the 5 first-choice classes.

However, this therapeutic decision should only be taken after checking the possible causes of ‘pseudo-resistance’:

1) poor compliance with the prescribed therapeutic regimen, especially if that regimen is complicated by administration frequencies of more than twice a day;

2) ‘alarm reaction’ to clinical measurement (the so-called ‘white coat effect’), which conditions the detection of high blood pressure values in the outpatient clinic in the face of good blood pressure control documented by correct home measurements or 24-hour blood pressure monitoring.

Certain therapeutic regimes seem particularly useful in resistant hypertension:

1) a long-acting ACE inhibitor combined with a calcium channel blocker and a loop diuretic (e.g. furosemide 25 mg x 2/day);

2) an alpha-1-blocker at an appropriate dosage combined with 2 other drugs of first choice. If what has been described so far represents the usual procedure in antihypertensive therapy on which there is a broad consensus, the peculiar empiricism of such therapy offers to the attention of the practising physician and the specialist two ever topical problems regarding pharmacological associations, both of which are the result of the fall of the dogmatic wall of ‘stepped’ therapy: the pharmacological association as the first therapeutic choice and fixed-dose pharmacological associations. If, as already mentioned, IAE is a multifactorial pathology and if, in order to obtain in hypertensives treated pharmacologically, rates of cardiovascular mortality and morbidity similar to those of normotensive patients, it is necessary to reduce blood pressure values to below the “golden” 140/90 mmHg, as the HOT Study (4) proposes, we cannot be scandalised if it is considered necessary to start antihypertensive therapy with the association of two drugs of first choice. Nor can one be scandalised if the pharmaceutical industry proposed the clinical trial and subsequent marketing of preparations containing a fixed-dose combination of these drugs. The only serious objection, relating to a possible different pharmacokinetics of the two components, is counterbalanced by the favourable impact on compliance, also recognised by the WHO (1).

And at this point we cannot tire of repeating how adherence to the prescribed therapy represents a very important problem in a pathology that runs asymptomatically until disorders related to cardiovascular complications or side effects of antihypertensive drugs occur.

Knowledge of the latter, especially of the more subtle (e.g. metabolic) ones, must be a further guide to a correct pharmacological combination, in order to be able to offset the side effects of one drug with those, the opposite, of another.

Examples include the ACE-inhibitor-diuretic association in relation to potassium and the beta-blocker-dihydropyridine association in relation to heart rate

Given that clinical experience shows that the combination of 2-3 antihypertensive drugs reduces blood pressure values in more than 80-90% of hypertensive patients (2), it would be fair to imagine that it would not be difficult to achieve good control of blood pressure values in the population.

However, epidemiological studies do not agree with such rosy predictions.

In the United States of America, in 1991, 82 per cent of the hypertensives treated had a blood pressure of 160/95 mmHg or less, but this percentage dropped to 55 per cent if a therapeutic goal of 140/90 mmHg or less was considered (5).

In Italy, a 1989 epidemiological study on the population of Gubbio showed acceptable blood pressure control (blood pressure equal to or below 160/95 mmHg) in only 47% of the hypertensives treated (6).

Similarly, although on a much more limited scale, a retrospective study, which used 24-hour blood pressure monitoring to verify therapeutic control in 135 hypertensive patients in the Rome area treated pharmacologically by their family doctors, showed average daytime blood pressure values equal to or lower than 135/85 mmHg in approximately 49% (7).

There is therefore a huge gap between the ideal therapeutic strategy to be followed in IAE and its practical application.

The main reason for this gap lies precisely in the poor dissemination of antihypertensive pharmacological associations outside specialist clinical settings due to limited scientific information (8).

Essential hypertension, bibliography

Guidelines Sub-Committee of the WHO/ISH Mild hypertension Liaison Committee: 1993

Guidelines for the management of mild hypertension: memorandum from a World Health Organization/International Society of Hypertension Meeting. J Hypertens 1993; 11: 905-918.

Mancia G and Grassi G: Combination treatment of hypertension. High Blood Press 1994; 3 (Suppl to No 4): 5-7.

Beevers DG and MacGregor GA: Schemes for reducing blood pressure. In: Beevers DG and MacGregor GA, Hypertension in Practice, 2nd Edition. London, Martin Dunitz, 1995, pp 175-177.

The HOT Study Group: The Hypertension Optimal Treatment Study. Blood Pressure 1993; 2: 62-68.

Burt VL, Cutler JA, Higgins M, Horan MJ, Labarthe D, Whelton P, Brown C, Roccella EJ: Trends in the prevalence, awareness, treatment, and control of hypertension in the adult US population. Data from the Health Examination Surveys, 1960 to 1991. Hypertension 1995; 26: 60-69.

Laurenzi M, Mancini M, Menotti A on behalf of the Gubbio Study Group: Multiple risk factors in hypertension: results from the Gubbio study. J Hypertens 1990; 8 (suppl 1): S7-S12.

Pannarale G, Villatico Campbell S, Pannitteri G, Serafini G, Farinelli A, Jacovoni A and Campa PP: Ambulatory blood pressure monitoring confirms “the rule of halves” (abstr). Am J Hypertens 1996; 9:71A.

Zanchetti A: Ipertensione arteriosa, linee guida e pratica clinica. La Cardiologia nella Pratica Clinica 1996; 3: 131-133.

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