Introduction

Until the early 1990’s the World Health Organization’s definition for the upper limit of a normal blood pressure was 160/95. Other hypertension professional bodies had similar views and it was widely accepted that treatment for lower levels of blood pressure was not beneficial ⁽¹⁾.

The quest for newer drugs for the treatment of hypertension continues. The ability to produce such new therapies stems from increasing knowledge of the different mechanisms that contribute to the production of hypertension.

This article will review the change in trends concerning the definition and guidelines for treatment of hypertension and highlight some of the newer therapies, which were recently introduced or are in the process of validation in clinical trials.

Evidence Review and Newer Concepts

The level to which the blood pressure should be lowered in patients with hypertension had been a matter of controversy. The two major issues of debate were the level at which maximal protection against cerebro- and cardiovascular events and renal damage could be achieved and whether harm could be produced by rather low levels of blood pressure i.e.: J-effect⁽²⁾. More recently data from different trials pointed towards linear relationship between increased protection and more aggressive blood pressure control to levels much lower than what had been accepted previously. Meta-analysis of data from 17 trials which examined the protective effect of anti-hypertensive therapy was published by MacMahon and Rodgers⁽³⁾ . Those trials included 47,653 patients with a mean age of 57 years and follow-up period of 4.9 years. The blood pressure was lowered by 10-12 mm Hg (systolic) and 5-6 mm Hg (diastolic) in the treated group compared to the control group. Although the blood pressure reduction was only very modest, there was a significant reduction of 38% in the incidence of cerebrovascular accidents and 16% decrease in coronary heart disease events.

In the Systolic Hypertension in the Elderly Programme (SHEP) benefit and safety were shown to occur with progressive reduction of both systolic and diastolic blood pressures but cardiac events were not stratified with the diastolic blood pressure levels and therefore, a J-effect could not be ruled out.

The Modification of Diet in Renal Disease (MDRD) study compared the rate of decline in glomerular filtration rate (GFR) in 840 patients with various chronic renal diseases who were randomized either to usual or low blood pressure goals (mean blood pressure 107 or 92 mm Hg). The rate of decline in GFR and the proteinuria were reduced in the low blood pressure group.

The Hypertension Optimal Treatment (HOT) trial was designed to assess the optimum target diastolic blood pressure and whether a J-effect exists. It was a large prospective multi-centre study that recruited 19,193 hypertensive patients, from 26 countries, aged 50-80 years (mean 61.5 years). The baseline diastolic blood pressure was between 100 and 115 mm Hg. They were assigned to three diastolic blood pressure target levels: ? 90 mm Hg, ? 85 mm Hg or ? 80 mm Hg. The calcium antagonist felodipine was used in all patients in step-wise dose increments with addition of other hypotensive agents as necessary to achieve the target blood pressures in each group⁽⁴⁾. The study gave some indication of the minimum blood pressure i.e. the values around which the maximum benefit of treatment can be expected, these being systolic 130 to 140 mm Hg and diastolic values between 80 and 85 mm Hg. Efforts to lower blood pressure further, to 120 mm Hg systolic and 70 mm Hg diastolic, did not confer further benefit, but did nor cause any significant additional risk i.e. there was no evidence of a J-effect for cardiovascular events, myocardial infarction, all stroke and cardiovascular mortality. The lowest achieved BP was 120 mm Hg systolic and 70 mm Hg diastolic.

A seven-country research group has recently published the results of a trial that investigated the relation between blood pressure and long-term mortality from coronary heart disease in which 12,031 men were followed-up for 25 years⁽⁵⁾. The relative risk from coronary heart disease was found to rise progressively with increasing levels of systolic and diastolic blood pressures. Sustained decrease of 10 mm Hg in systolic and 5 mm Hg in diastolic blood pressures were each associated with a 28% drop in the risk of death from coronary heart disease. Interesting findings in the results of this trial are the absence of abrupt increase in the mortality risk above the blood pressure levels typically used as criteria for hypertension and the absence of a clearly defined lower level of blood pressure below which the risk did not continue to decline. Any difference in blood pressure between persons is associated with approximately constant difference in relative risk from coronary heart disease irrespective of whether they have hypertension or not.

Such cumulative data have led the professional organizations concerned with hypertension to establish new definitions for hypertension and guidelines for treatment. The Joint National Committee for the Prevention, Detection, Evaluation and Treatment of High Blood Pressure 6^th report (JNC-6) expressed those new developments and similar guidelines were published by the International Society of Hypertension and the World Health Organization (ISH-WHO). The JNC-6⁽⁶⁾ uses the following classification:

* Optimal blood pressure = systolic ? 120 and diastolic ? 80 mm Hg

* Normal blood pressure = systolic 120-129 and diastolic 80-84 mm Hg

* High-normal blood pressure = systolic 130-139 or diastolic 85-89 mm Hg

* Hypertension:

? Stage 1 = systolic 140-159 or diastolic 90-99 mm Hg

? Stage 2 = systolic 160-179 or diastolic 100-109 mm Hg

? Stage 3 = systolic ? 180 or diastolic ? 110 mm Hg

The systolic and diastolic pressures are of equal importance; if there is a disparity in category, the higher value determines the blood pressure class or the severity of hypertension. When considering treatment this classification takes in consideration other major risk factors (smoking, dyslipidaemia, diabetes mellitus, age above 60 years and family history of cardiovascular disease) and target organ damage. Even in the high normal group drug therapy is recommended if heart failure, diabetes mellitus or renal insufficiency co-exist.

Microalbuminuria has emerged as an important risk marker in hypertension indicative of end-organ damage. It is a predictor for the development of premature coronary vascular disease in diabetics, development of clinical proteinuria and progression of renal damage. It is best measured on a timed urine collection but early morning or random urine specimens can be used. Accuracy can be increased by calculating the albumin creatinine excretion ration.

Newer Drug Therapies

1. Angiotensin II Receptor Antagonists

Angiotensin II (A II ) is produced in plasma by the sequential processing of circulating angiotensinogen by renin and Angiotensin I Converting Enzyme (ACE). Renin, produced by the kidney, is a major factor in regulating the production of A II in the circulation. Recently it has been recognized that local A II production also occurs in several tissues such as the brain, adrenal glands, the heart and blood vessels. In these tissues A II levels are regulated by uptake of A II from the circulation as well as by local formation and degradation of A II via a tissue renin angiotensin system (RAS). In the tissues Chymase and other enzymes convert angiotensin I (A I ) to A II in a process independent of blood ACE. In animal experiments ACE inhibition reduced basal A II formation by only 25%. A II receptor antagonists selectively compete with the binding of A II to its type I (AT₁ ) receptor. AT₁ receptor is present in all tissues and is responsible for most of the known actions of A II . The first four A II receptor antagonists are:

Losartan which produces a short surmountable AT₁ receptor blockade but its metabolite, EXP 3174, has a long duration of action and produces an insurmountableAT₁ blockade. It is 20 times more potent than the parent drug⁽⁷⁾.

Valsartan is also a potent AT₁ antagonist. The parent compound is the active drug. It has a half-life of 6-9 hours and is excreted in bile (70%) and by the kidneys (30%)⁽⁸⁾.

Irbesartan and Candesertan are long acting and produce insurmountable A II blockade. Irbesartan has a half-life of 11-15 hours, and is mainly cleared by the liver (78%) and by the kidneys (22%)⁽⁹⁾. Candesertan is a pro-drug and unlike other A II receptor antagonists, is cleared mainly by the kidneys (60%)⁽¹⁰⁾. Those latter two drugs differ from Losartan and Valsartan in that they have a clear dose-response relationship, which was not established with Losartan or Valsartan.

When A II receptor antagonists were compared with other hypotensive drugs, they were found to have an efficacy equivalent to that of ACE inhibitors, calcium antagonists and B-blockers^(,7,8,9,10). When the RAS is blocked, blood pressure becomes salt sensitive; thus diuretics enhance the BP lowering effect of A II antagonists. This has been demonstrated in several clinical studies⁽¹¹⁾. A II receptor antagonists as a class have excellent tolerability profile with an incidence of side effects similar to that of placebo. Unlike the ACE inhibitors, they do not induce cough. The only interclass difference is the ability of Losartan to increase urinary uric acid excretion and lower plasma uric acid.

Combining ACE inhibitors and A II receptor antagonists:

Long term use of ACE inhibitors produces marked elevation of A I in the circulation because its conversion to A II is blocked . This excessively available A I is taken by the tissue enzymes and is converted to A II locally giving A II actions which by-pass the circulation ACE block. Therefore the use of A II receptor antagonists to block the effect of this local A II on the AT₁ receptor can be complementary to the use of ACE inhibitors enhancing the hypotensive effect. In spite of this potential beneficial combination, the combined use of ACE inhibitors and A II receptor antagonists in the treatment of hypertension has not been thoroughly studied in well designed controlled trials. A preliminary study conducted on normotensive volunteers has suggested that combined administration of an ACE inhibitor and A II receptor antagonist induces an additional blood pressure reduction⁽¹¹⁾. On the other hand other therapeutic benefits of the combination of ACE inhibitors and A II receptor antagonists have been probed: in a pilot study on anterior myocardial infarction, the authors concluded that the addition of Losartan to Captopril improved the beneficial effects of ACE inhibition in patients with anterior myocardial infarction⁽¹²⁾. The effect of the combination was also studied on proteinuria: the use of the combination produced more reduction in proteinuria than that which was effected by ACE inhibition or A II receptor antagonism alone. The main drawback of this study is the small number of patients⁽¹³⁾.

(B)Endothelin antagonists.

The Endothelins encompass a family of three 21-amino acid isopeptides ET 1,2,3. The most important, Endothelin-1 (ET-1), is produced by endothelial, mesangial, glomerular epithelial and medullary collecting duct cells. The final step in the formation of ET-1 is the cleavage of Proendothelin (big ET) by an Endothelin-converting enzyme (ECE) (Fig1). ET-1 is the most potent endogenous vasoconstrictor yet identified: it is hundred times more potent than norepinephrine when compared on equimolar basis. It acts on two main receptors: ETa and ETb. Stimulation of the former receptor is responsible for the vasoconstrictive effect of ET-1, while ETb has a vasodilator effect conducted through stimulating the production of nitric oxide and prostaglandins. ET-1 is implicated in the pathogenesis of hypertension and its level was elevated in some of the studies on patients with essential hypertension⁽¹⁴⁾. It was also found to contribute to increased vascular tone ⁽¹⁵⁾.

Drugs against ET-1 have been developed with their actions mainly exerted at two sites: ET receptor and ECE.

(i) ET receptor antagonist: the first member of this class is Bosentan, an orally administered blocker of both ETa and ETb receptors. Initial trials have shown it to be effective in lowering blood pressure⁽¹⁶⁾. In a dose of 100 to 500 mg per day it was found to produce a blood pressure lowering effect equivalent to Enalapril 20mg per day. Doses of up to 2000 mg were well tolerated but contributed no additional therapeutic benefit. An additional advantage of Bosentan is the absence of reflex increase in heart rate, norepinephrine blood level, plasma renin activity or angiotensin II . This could have important useful implications in cardiovascular disease particularly in patients with heart failure^(16,17). The main adverse effects were headache, flushing and lower limb oedema. No serious side effects were reported. New ET receptor antagonists are being developed, some of which like BQ-123 are specific to the ETa receptor which is likely to make them more potent hypotensive agents (Fig 2). ET antagonists are likely to create a new class of hypotensive drugs, which will widen the range of our armamentarium for the treatment of hypertension.

(ii) ECE inhibitors: Phosphoramidon is the first ECE inhibitor but has other non-specific actions. More selective agents are being developed by a number of pharmaceutical firms.

Genetics and Hypertension

With the development in molecular biology, the field of genetics is progressing rapidly. Some developments are helping in the understanding of the pathophysiology and management of hypertension. Examples of such developments are:

1. ACE Gene and I/D Polymorphism
With DNA cloning it was possible to identify the structure of the ACE gene with 26 exons and spans 21 Kb on chromosome 17 ⁽¹⁸⁾. I/D polymorphism consists of the presence (Insertion -I-) or absence (Deletion - D -) of 287 base pair fragments in intron 16 resulting in 3 genotypes: Insertion homozygotes (II), Insertion/Deletion heterozygotes (ID) and Deletion homozygotes (DD).

II individuals have relatively low plasma concentrations of ACE compared to DD individuals who have high levels, while the heterozygotes ID have intermediate plasma ACE levels.

The DD genotype has been linked to essential hypertension, left ventricular hypertrophy and development of nephropathy in insulin and non-insulin-dependent diabetes mellitus. It may also be a potential genetic marker in hypertensives at risk of renal complications ⁽¹⁹⁾ .

Unlike the DD geneotype, which has good antiproteinuric response to ACE inhibitors, the II genotype response is limited. This could be explained by the fact that the II has naturally low plasma ACE levels allowing no significant drop with the use of ACE inhibitors.
 

2. AT II Type 1 Receptor (AT₁) Polymorphism

Conclusion

Trends have changed concerning the definition of hypertension, the levels of blood pressure at which treatment should be started and the target levels of treatment. Associated risk factors are given more weight in the management of patients with hypertension emphasizing the importance of multifactorial aetiology in the production of cerebro- and cardiovascular disease. The effort to introduce newer classes of drugs for the treatment of hypertension continues giving physicians more options as far as efficacy and avoidance of adverse effects are concerned.

With the developments in molecular biology the field of genetics is rapidly progressing which may help in understanding the pathophysiology and in the management of hypertension.

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