Methods and Findings in Experimental and Clinical Pharmacology
Vol. 24, Suppl. A, 2002, pp. 13
ISSN 0379-0355
Copyright 2002 Prous Science, S.A.
CCC: 0379-0355/2002
http://www.prous.com

New Drugs in the Management of Arterial Hypertension

J. Tamargo

Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Spain

Hypertension is poorly controlled in a high proportion of patients, despite the availability of a variety of antihypertensive agents. Thus, there is a great need for new antihypertensive drugs that better control blood pressure and reduce other risk factors. Recent advances in the understanding of the pathogenesis of hypertension has led to the development of a large number of new antihypertensive drugs that target receptors, enzymes and channels (Table 1). These agents should prevent target-organ damage independently of blood pressure reductions, as well as extend therapeutic options for patients inadequately controlled with current hypertension pharmacotherapy.

Because hypertension is essentially a polygenic disease, new drugs with multiple mechanisms of action can be expected to control blood pressure in a greater proportion of patients. Vasopeptidase inhibitors, which simultaneously inhibit both angiotensin-converting enzyme and neutral endopeptidase, may offer more choices for therapy. Another strategy is to improve the efficacy:side effects ratio of existing antihypertensive drugs by developing low-dose combinations of agents that lower blood pressure by different mechanisms.

Gene therapy based on either the overexpression of vasodilatory genes (atrial natriuretic peptide, kallikrein, adrenomedullin, NO synthase) or the inhibition of vasoconstrictory genes (renin-angiotensin system, endothelin, adrenergic receptors and L-type Ca channels) is a new exciting pharmacotherapeutic approach. Signaling molecule-related genes (protein kinase A/G or SERCA) and genes relevant to matrix proteins all offer interesting possibilities as potential targets for gene therapy. However, optimistic evaluation of the results should be tempered by the transient and modest nature of therapeutic response, which may reflect the multifactorial nature of the disease as well as limited gene transfer efficiency. Additionally, extensive experiments must be carried out to establish the mechanisms, and new and safe viral vectors with high transduction efficiency must be developed.

One of today's most important considerations in drug development is pharmacogenomics­the recognition that kinetics and dynamics of a given drug vary significantly from person to person because of genotypic variations. Progress is being made with candidate gene and genome scanning approaches, as they identify and characterize genes influencing the pharmacodynamic mechanisms that contribute to interindividual differences in antihypertensive drug therapy responses. A better knowledge of genes that contribute to hypertension and genes that influence drug responses will undoubtedly serve as a starting point for the development of patient-specific antihypertensive therapy, which will mean safer and more effective treatment and prevention of hypertension and its associated target-organ diseases.

Methods and Findings in Experimental and Clinical Pharmacology Vol. 24, Suppl. A, 2002, pp. 13
ISSN 0379-0355 Copyright 2002 Prous Science, S.A. CCC: 0379-0355/2002 http://www.prous.com