Current Pharmaceutical Design - Volume 9, Issue 21, 2003

Management of hypertension has evolved steadily through 25 years of major clinical trials results modifying both the definition of hypertension and clinical management strategies. Trials experience in heart failure is much less extensive given the far smaller therapeutic market and traditionally often followed on the establishment of an agent or class of therapy in hypertension. Separate product profile development in heart failure is rare. Large outcome trials in heart failure are markedly smaller than those in hypertension and have tended to be confined to the last 15 years or so. There are clear examples of agents developed and successful in clinical use in both conditions but more recently the divergence of trials results in the two conditions has shown that comparable efficacy is no longer something which can be taken for granted. This review considers the past successes and more recent contrasts which have emerged in these traditional areas of pharmacological development.

The combination of investigation of rare Mendelian forms of hypertension, candidate gene studies, comparative mapping and genome-wide screening in both animal models and man has led to significant progress in determining new mechanisms of blood pressure control. In this review, the newly discovered blood pressure / cardiovascular genes, WNK kinases and angiotensin converting enzyme 2 and the development of a new anti-hypertensive agent PST2238 are discussed. Major genes causing essential hypertension have yet to be discovered, however, there are now over 20 published genome-wide screens for blood pressure controlling genes. Several regions demonstrate suggestive linkage to the trait and there is some overlap of regions between the different studies. It is hoped that new blood pressure genes will ultimately be discovered using this method. Pharmacogenetic studies in hypertension have only been initiated recently, some are described in this paper. Small studies upon single candidate genes, suggest that the contribution of genetics to the inter-individual variation in blood pressure response to anti-hypertensive therapy, is small, approximately 3-5%. Recently micro-arrays with multiple polymorphisms in multiple genes have been used. After accounting for the additive affects of multiple blood pressure loci, an individual's genetic profile appeared to explain up to 50% of the variation in blood pressure response to therapy. Knowledge of the genetic variants that cause hypertension and influence response to anti-hypertensive therapy will ultimately provide a greater understanding of the molecular mechanisms underlying blood pressure control.

Physiological and pharmacological responses may be influenced by ethnicity as a result of genetic factors, environmental factors and / or their interaction. This review is divided into 2 parts. Firstly, there will be overview of ethnicity as a determinant of drug metabolism and response with reference to antihypertensive agents. The concept of ethnicity has been applied extensively to the study of hypertension especially in American blacks in whom the hypertension is more common and more aggressive. Thus, the second part of this review will then focus on examining the black-white differences in physiological responses to pharmacological challenge that may provide a link between these models and known ethnic differences in drug responses. We will discuss the hypertension studies that have examined the relative effectiveness of different classes of antihypertensive agents including several recent cardiovascular outcome trials that either have a high proportion of blacks or were conducted entirely in black subjects.

Hypertension and cardiac arrhythmias commonly coexist in many patients. In this review, we will initially discuss arrhythmogenesis in hypertension, with particular emphasis on atrial and ventricular tachyarrhythmias and sudden cardiac death, whilst in the final part, we will focus our attention on the effects of anti-hypertensive therapies on supra-ventricular and ventricular arrhythmias and on sudden cardiac death prevention. Many patients with atrial fibrillation or frequent premature ventricular contractions have hypertension, and both need to be managed appropriately. Furthermore, hypertensive left ventricular hypertrophy could cause a wide variety of ventricular arrhythmias, which could end in sudden cardiac arrest. Most anti-hypertensive therapies, such as the β-blockers or ACE inhibitors, by slowing or interrupting the progression towards atrial and ventricular remodelling might exert some anti-arrhythmic effect, thus reducing the risk of sudden cardiac death in these patients.

Hypertension is associated with the flow of blood under high pressures, yet the complications of hypertension, such as myocardial infarction or stroke are paradoxically thrombotic rather than haemorrhagic. This could be explained by increasing evidence which suggests that hypertension fulfils the pre-requisites of the Virchow's triad for thrombogenesis, leading to a prothrombotic or hypercoagulable state. Hypertension leads to changes in the platelets, endothelium and the coagulation and fibrinolytic pathways which help to promote the induction and the maintenance of this prothrombotic state. These changes can to a certain extent be reversed by the treatment of hypertension, although different antihypertensive agents may have variable effects in reversing these changes. Some of the effects may be simply related to normalisation of blood pressure, but certain groups of drugs such as those acting on the renin-angiotensin-aldosterone system appear to have an effect over and above this. Anti-platelet agents have also been shown to confer a degree of benefit to ‘high risk’ hypertensive patients. The study of the prothrombotic state in hypertension is therefore of paramount importance, as understanding the pathogenic processes underlying it can help prevent many of the complications associated with this condition.

Arterial Hypertension (AH) is characterized by reduced nitric oxide (NO) biosynthesis, activation of the Renin- Angiotensin-Aldosteron-System (RAAS), vasoconstriction, and microvascular rarefaction. The latter contributes to target organ damage, especially in left ventricular hypertrophy, and may partially be due to impaired angiogenesis. Angiogenesis, the formation of new microvessels and microvascular networks from existing ones, is a highly regulated process that arises in response to hypoxia and other stimuli and that relieves tissue ischemia. In AH, angiogenesis seems impaired. However, blood pressure alone does not affect angiogenesis, and microvascular rarefaction is present in normotensive persons with a family history for AH. Normal or increased NO in several processes and diseases enables or enhances angiogenesis (e.g. in portal hypertension) and reduced NO biosynthesis (for example, in a rat model of AH, in other disease models in vivo, and in endothelial NO Synthase knock out mice) impairs angiogenesis. Angiogenic growth factors such as Vascular Endothelial Growth Factor (VEGF) and Fibroblast Growth Factor (FGF) induce NO and require NO to elicit an effect. Effector molecules and corresponding receptors of the RAAS either induce (Bradykinin, Angiotensin II) or perhaps inhibit angiogenesis. The pattern of Bradykinin- and Angiotensin II-receptor expression and the capacity to normalize NO biosynthesis may determine whether ACE-inhibitors, Angiotensin II-receptor antagonists and other substances affect angiogenesis. Reconstitution of a normally vascularized tissue by reversal of impaired angiogenesis with drugs such as ACE inhibitors and AT1 receptor antagonists may contribute to successful treatment of hypertension-associated target organ damage, e.g. left ventricular hypertrophy.

The hypertensive disorders of pregnancy complicate 5-10% of pregnancies. Of these disorders 70% are pregnancy related (preeclampsia-eclampsia and gestation hypertension) and 30 % are a pre-existing hypertensive condition (chronic hypertension). These disorders are associated with maternal and fetal complications and have a substantial economic impact. This review examined the pharmacological treatment of the hypertensive disorders of pregnancy. There is a general consensus that anti-hypertensive should be given with severe hypertension and this should be in the hospital. The value of antihypertensive drugs in pregnant women with mild hypertension continues to be an area of debate that the evidence is too scanty to securely evaluate the clinical benefits of treating mild hypertension during pregnancy. The choice of the antihypertensive agents depends on individual clinician preference, the specified maternal and foetal benefits and the reproductive complications (teratogenisity, fetotoxicity and neonatal toxicity) of each particular agent. There are unequivocal evidences that Magnesium sulphate is superior to other agents in reducing recurrent eclamptic seizures. There is a strong recent evidence recommended that magnesium sulphate should be considered for women with pre-eclampsia for whom there is concern about the risk of eclampsia.