ANGIOTENSIN II RECEPTOR BLOCKERS: AN OVERVIEW Review Article AMIT K. KHAIRNAR*, DHEERAJ T. BAVISKAR 1 , DINESH K. JAIN 2 1 KVPS Institute of Pharmaceutical Education, Boradi, Tal- Shirpur, Dist-Dhule, 425428 (M.S.), 2 Received: 16 Dec 2010, Revised and Accepted: 25 Sep 2011 College of pharmacy, I.P.S. Academy, Rajendra Nagar, Indore, 452012 (M.P.) India. *Email: amitkhairnar_2004@yahoo.co.in ABSTRACT Blockage of the renin-angiotensin system (RAS) is now recognized as an effective approach to the treatment of hypertension and congestive heart failure. Today, it is possible to antagonize the effects of angiotensin II (AT-II) more specifically by blocking its receptors by using nonpeptide receptor antagonists. AT-II-receptor antagonists were developed as agents that would more completely block the RAS and thus decrease the adverse effects seen with Angiotensin Converting Enzyme (ACE inhibitors). AT-II-receptor antagonists include losartan, valsartan, irbesartan, candesartan, eprosartan and telmisartan. The adverse effects of AT-II-receptor antagonists dizziness, headache, upper-respiratory- tract infection, cough, and gastrointestinal disturbances occur at about the same rate as with placebo. Four of them have recently been launched on the market and several others are preregistered for the treatment of hypertension. These new molecules are as effective as ACE inhibitors, calcium antagonists and beta-blockers in lowering blood pressure in hypertensive patients. When compared to ACE inhibitors, they appear to have comparable favorable effects on systemic and renal hemodynamic properties. All available AT-II-receptor antagonists seem to be equally effective in reducing both systolic and diastolic blood pressure. Currently, AT-II-receptor antagonists are used either as monotherapy in patients who cannot tolerate ACE inhibitors or in combination with other antihypertensive agents. In this review we summarize the combined therapy of ACE inhibitors and AT-II receptor antagonists play in ischemic heart disease. In this respect the review will improve ideas for developing new formulations with combinations of these drugs in the future. Keywords: Renin-angiotensin system, Hypertension, Angiotensin II receptor, Angiotensin Converting Enzyme inhibitors. INTRODUCTION Hypertension is not a single disease but a syndrome with multiple causes. In most instances, the cause remains unknown, and the cases are lumped together under the term essential hypertension (Table 1). However, mechanisms are continuously being discovered that explain hypertension in new subsets of the formerly monolithic category of essential hypertension, and the percentage of cases in the essential category continues to decline. Essential hypertension is often called primary hypertension, and hypertension in which the cause is known is called secondary hypertension, although this separation seems somewhat artificial. This chapter discusses the pathogenesis of hypertension and its complications in general terms and then discusses the specific causes of the currently defined subgroups and the unique features, if any, that each adds to the general findings in patients with high blood pressure. Table 1: Estimated frequency of various forms of hypertension in the general hypertensive population. S. No. 1 Type of hypertension % Population 1. Essential hypertension 88.0 2. Renal hypertension 2.1 Renovascular 2.0 2.2 Parenchymal 3.0 3. Endocrine hypertension 3.1 Primary aldosteronism 5.0 3.2 Cushing's syndrome 0.1 3.3 Pheochromocytoma 0.1 3.4 Other adrenal forms 0.2 3.5 Estrogen treatment (contraceptive hypertension) 1.0 3.6 Miscellaneous (Liddle's syndrome, coarctation of the aorta, etc) 0.6 ABNORMALITIES OF THE RENIN-ANGIOTENSIN SYSTEM Increased secretion of angiotensinogen from the liver can cause hypertension. Secretion of this angiotensin precursor is under endocrine control and is stimulated by estrogens. Consequently, it is increased in women taking contraceptive pills containing large amounts of estrogens. When circulating angiotensinogen is increased, more angiotensin II is formed and blood pressure rises. The normal compensation for this response is decreased secretion of renin because angiotensin II feeds back directly on the juxtaglomerular cells to reduce renin secretion. However, in some women, the compensation is incomplete and the estrogens cause a significant increase in blood pressure. The incidence of this pill hypertension in the general hypertensive population is about 1% (Table 1). Some of the women with the condition have underlying essential hypertension, which is triggered by the estrogens, but in others the hypertension is cured by stopping estrogen treatment. Mutations in the gene for angiotensinogen, which produce slight increases in circulating angiotensinogen, have been reported to be more common in patients with essential hypertension than in individuals with normal blood pressure. The renin-angiotensin-aldosterone cascade is activated when renin, secreted by the juxtaglomerular cells of the kidneys, catalyzes the conversion of angiotensinogen to angiotensin I (AT-I) in the liver. AT-I is locally transformed into active AT-II via ACE. AT-II, a peptide hormone, is responsible for numerous effects, aldosterone production and release, afferent and efferent vasoconstriction, proximal tubular reabsorption of sodium, increased inotropism and chronotropism, stimulation of drinking behavior and sodium appetite, vagus suppression, and b-adrenergic-receptor stimulation. Two subtypes of AT-II receptors have been identified. Type 1 receptors are predominantly found on vascular endothelium and are linked to all the known physiological and pharmacologic actions of AT-II. Stimulation of type 1 receptors by AT-II induces vasoconstriction, renal tubular sodium reabsorption, aldosterone release, vascular smooth muscle remodeling, and stimulation of central and peripheral sympathetic activity, thus leading to increases in blood volume and blood pressure. 1 The Renin-Angiotensin Receptor System 2 Antagonism of type 1 receptors lowers blood pressure by inhibiting these actions. Type 2 receptors are predominantly found in the adrenal medulla, uterus, and fetal tissue and may play a role in fetal growth and differentiation, although the exact function of these receptors has not been identified. 3 International Journal of Pharmacy and Pharmaceutical Sciences ISSN- 0975-1491 Vol 4, Suppl 3, 2012 A A c c a a d d e e m mi i c c S Sc c i i e e n n c c e e s s