Angiotensin Receptors and Their Antagonists

289

215

Angiotensin II receptor blockers (ARBs) represent a new class of effective and well tolerated orally active antihypertensive agents. Recent clinical trials have shown the added benefits of ARBs in hypertensive patients (reduction in left ventricular hypertrophy, improvement in diastolic function, decrease in ventricular arrhythmias, reduction in microalbuminuria, and improvement in renal function), and cardioprotective effect in patients with heart failure. Several large long-term studies are in progress to assess the beneficial effects of ARBs on cardiac hypertrophy, renal function, and cardiovascular and cerebrovascular morbidity and mortality in hypertensive patients with or without diabetes mellitus, and the value of these drugs in patients with heart disease and diabetic nephropathy.The ARBs specifically block the interaction of angiotensin II at the AT 1 receptor, thereby relaxing smooth muscle, increasing salt and water excretion, reducing plasma volume, and decreasing cellular hypertrophy. These agents exert their blood pressure-lowering effect mainly by reducing peripheral vascular resistance usually without a rise in heart rate. Most of the commercially available ARBs control blood pressure for 24 h after once daily dosing. Sustained efficacy of blood pressure control, without any evidence of tachyphylaxis, has been demonstrated after long-term administration (3 years) of some of the ARBs. The efficacy of ARBs is similar to that of thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors or calcium channel blockers in patients with similar degree of hypertension. Higher daily doses, dietary salt restriction, and concomitant diuretic or ACE inhibitor administration amplify the antihypertensive effect of ARBs. The ARBs have a low incidence of adverse effects (headache, upper respiratory infection, back pain, muscle cramps, fatigue and dizziness), even in the elderly patients. After the approval of losartan, five other ARBs (candesartan cilexetil, eprosartan, irbesartan, telmisartan, and valsartan) and three combinations with hydrochlorothiazide (irbesartan, losartan and valsartan) have been approved as antihypertensive agents, and some 28 compounds are in various stages of development.The ARBs are non-peptide compounds with varied structures; some (candesartan, losartan, irbesartan, and valsartan) have a common tetrazolo-biphenyl structure. Except for irbesartan, all active ARBs have a carboxylic acid group. Candesartan cilexetil is a prodrug, while losartan has a metabolite (EXP3174) which is more active than the parent drug. No other metabolites of ARBs contribute significantly to the antihypertensive effect.Keywords: angiotensin receptor blockers; candesartan; eprosartan; irbesartan; losartan; telmisartan; valsartan; pharmacokinetics After oral administration, the ARBs are rapidly absorbed (time for peak plasma levels ‫؍‬ 0.5-4 h) but they have a wide range of bioavailability (from a low of 13% for eprosartan to a high of 60-80% for irbesartan); food does not influence the bioavaila...

Section: Mechanism Of Blood Pressure Lowering Action Of Angiotensin Rmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension

2000

289

215

“…Members of this new class have been proved effective in the treatment of hypertension and have recently also shown promise for the treatment of heart failure. AIIRAs attenuate the effects of angiotensin II by blocking its action, competitively or non-competitively, at the AT 1 receptor. This receptor subtype mediates the cardiovascular and metabolic activities of angiotensin II.…”

Section: Antihypertensive Therapymentioning

confidence: 99%

“…This receptor subtype mediates the cardiovascular and metabolic activities of angiotensin II. 1 This mode of action contrasts with that of angiotensin-converting enzyme (ACE) inhibitors, which partially inhibit the conversion of angiotensin I to angiotensin II. One of the disadvantages of ACE inhibitors is that angiotensin II is also produced by non-ACE-dependent pathways, notably those involving chymase in the heart and other tissues.…”

Section: Antihypertensive Therapymentioning

confidence: 99%

Key features of candesartan cilexetil and a comparison with other angiotensin II receptor antagonists

Sever

1999

Current research on angiotensin II AT 1 -receptor antagonists (AIIRAs) and selected studies presented at the recent symposium held in Amsterdam, The Netherlands, on 6 June 1998, titled 'Angiotensin II Receptor Antagonists are NOT all the Same' are reviewed. AIIRAs offer a number of potential advantages over alternative antihypertensive agents acting via the renin-angiotensin-aldosterone system. They combine blood pressure-lowering effects at least equivalent to those of angiotensin-converting enzyme (ACE) inhibitors, coupled with placebolike tolerability. Candesartan cilexetil is a novel AIIRA that has demonstrated clinical efficacy superior to losartan, has a sustained duration of action over 24 hours (trough:peak ratio close to 100%) and is well tolerated Keywords: candesartan cilexetil; angiotensin II AT 1 -receptor antagonist; organ protection; review Antihypertensive therapyNon-peptide angiotensin II AT 1 -receptor antagonists (AIIRAs) are a new class of drugs that represent a major advance in therapeutics for the treatment of cardiovascular disease. Members of this new class have been proved effective in the treatment of hypertension and have recently also shown promise for the treatment of heart failure. AIIRAs attenuate the effects of angiotensin II by blocking its action, competitively or non-competitively, at the AT 1 receptor. This receptor subtype mediates the cardiovascular and metabolic activities of angiotensin II. 1 This mode of action contrasts with that of angiotensin-converting enzyme (ACE) inhibitors, which partially inhibit the conversion of angiotensin I to angiotensin II. One of the disadvantages of ACE inhibitors is that angiotensin II is also produced by non-ACE-dependent pathways, notably those involving chymase in the heart and other tissues. 2 The more specific mechanism of action of AIIRAs means that the actions of angiotensin II are completely blocked at the effector site, independently of the route of its production. Moreover, because ACE is identical to the enzyme kininase II, which inhibits bradykinin formation, AIIRAs avoid the bradykinin potentiation induced by ACE inhibitors and the in patients with essential hypertension. Candesartan cilexetil has a rapid onset of action (approximately 80% of total blood pressure reduction within the first 2 weeks) and dose-dependent effects on blood pressure, is comparable in efficacy to a number of classes of antihypertensives, and is effective in combination therapy (eg, with hydrochlorothiazide and amlodipine). This favourable profile may be due in part to the highly selective, tight binding to and slow dissociation of candesartan from the AT 1 receptor. Preliminary studies suggest that candesartan cilexetil also protects end organs (kidney, heart, vasculature, and brain) beyond blood pressure control.

“…RAS inhibitors reduce BP in hypertensive conditions marked by elevated PRA. 6 However, renin inhibitors, 7 converting enzyme inhibitors 6 and more recently ANG II receptor antagonists 8 can lower BP levels during hypertension even if PRA is low or within the normal range. Such results and information brought by molecular biology led to the discovery of local paracrine RASs in diverse tissues such as the arterial wall, kidney, heart, adrenal cortex and central nervous system, which may be regulated independently from their circulating counterparts.…”

Section: Introductionmentioning

confidence: 99%

Effects of transplantation on the renin angiotensin system (RAS)

Farge

Julien

1998

Hypertension in organ transplant recipients is associated with several functional modifications of the renin angiotensin system (RAS), which varies according to the type of transplanted organs (kidney, heart, liver or bone marrow) and the immunosuppressive regimen. Before transplantation, chronic organ failure is associated with direct and indirect stimulation of both systemic and local RASs. After transplantation, cyclosporin per se is the major determinant of hypertension. It induces