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Angiotensin II receptor blockers represent a class of effective and well tolerated orally active antihypertensive drugs. Activation of AT(1) receptors leads to vasoconstriction, stimulation of the release of catecholamines and antidiuretic hormone and promote growth of vascular and cardiac muscle. AT(1) receptor blockers antagonise all those effects. Losartan was the first drug of this class marketed, shortly followed by valsartan, irbesartan, telmisartan, candesartan, eprosartan and others on current investigation. All these drugs have the common properties of blockading the AT(1) receptor thereby relaxing vascular smooth muscle, increase salt excretion, decrease cellular hypertrophy and induce antihypertensive effect without modifying heart rate or cardiac output. Most of the AT(1) receptor blockers in use controlled blood pressure during the 24 h with a once-daily dose, without evidence of producing tolerance to the antihypertensive effect and being with low incidence of side effects even at long term use. Monotherapy in mild-to-moderate hypertension controls blood pressure in 40 to 50% of these patients; when a low dose of thiazide diuretic is added, 60-70% of patients are controlled. The efficacy is similar to angiotensin-converting enzyme (ACE) inhibitors, diuretics, calcium antagonists and beta-blocking agents. AT(1) receptor blockers are specially indicated in patients with hypertension who are being treated with ACE inhibitors and developed side effects such as, cough or angioedema. The final position in the antihypertensive therapy in this special population and other clinical situations, such as left ventricular hypertrophy, heart failure, diabetes mellitus and renal disease, has to be determined in large prospective clinical trials, some of which are now being conducted and seem promising.
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PMID:Angiotensin II receptor antagonists role in arterial hypertension. 1198 4

In well designed studies in patients with mild to moderate hypertension, combinations of the sustained-release (SR) formulation of the nondihydropyridine calcium channel antagonist verapamil 120 to 240 mg/day and the ACE inhibitor trandolapril 0.5 to 8 mg/day were significantly more effective in reducing sitting systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline than placebo. In most randomised studies, combinations of verapamil SR 120 to 240 mg/day and trandolapril 0.5 to 8 mg/day were significantly more effective in lowering sitting DBP and SBP than the corresponding monotherapies administered at the same dosage. Trandolapril/verapamil SR 2/180 mg/day provided significantly more effective 24-hour ambulatory blood pressure (BP) control than of the corresponding monotherapies. Moreover, trandolapril/verapamil SR reduced BP in patients inadequately controlled with either of the corresponding monotherapies. The antihypertensive efficacy of trandolapril/verapamil SR 2/180 mg/day was generally similar to that of other combinations of antihypertensive agents (metoprolol/hydrochlorothiazide, atenolol/chlorthalidone, lisinopril/hydrochlorothiazide, enalapril/hydrochlorothiazide) in patients with hypertension, including those with type 2 diabetes mellitus. Trandolapril/verapamil SR reduced BP in patients with hypertension and type 2 diabetes or primary renal disease, Black patients and elderly patients. Trandolapril/verapamil SR was more effective than the individual components administered as monotherapy in reducing proteinuria in patients with type 2 diabetes or primary renal disease. Trandolapril/verapamil SR had a neutral or beneficial effect on metabolic parameters (glucose, insulin, lipids) in patients with hypertension, including those with type 2 diabetes. Trandolapril/verapamil SR preserved left ventricular function in patients with heart failure. Fewer cardiac events occurred after therapy with trandolapril/verapamil SR than after trandolapril alone in post-myocardial infarction patients with congestive heart failure. The incidence of adverse events in recipients of trandolapril/verapamil SR was similar to that of the individual components, and that of other combination therapies. In placebo-controlled trials conducted in the US, headache, upper respiratory tract infections, cough, constipation, atrioventricular block (first degree) and dizziness were the most commonly reported adverse events in recipients of combinations of verapamil SR (120 to 240 mg/day) and trandolapril (0.5 to 8 mg/day). In conclusion, the fixed-dose combination of trandolapril/verapamil SR is an effective treatment for patients with hypertension, including those with type 2 diabetes. Trandolapril/verapamil SR tended to be more effective than monotherapy with either verapamil SR or trandolapril, and generally showed antihypertensive efficacy similar to that of other combination antihypertensive therapies. Current data support the use of trandolapril/verapamil SR as an alternative treatment when monotherapy with either agent is not effective. Data from large clinical trials currently being conducted will assist in fully defining the role of trandolapril/verapamil SR as a cardio- and renoprotective agent.
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PMID:Fixed combination trandolapril/verapamil sustained-release: a review of its use in essential hypertension. 1242 Nov 12

Both angiotensin-converting enzyme (ACE) inhibitors and AT-1 receptor antagonists reduce the effects of angiotensin II, however they may have different clinical effects. This is because the ACE inhibitors, but not the AT-1 receptor antagonists, increase the levels of substance P, bradykinin and tissue plasminogen activator. The AT-1 receptor antagonists, but not the ACE inhibitors, are capable of inhibiting the effects of angiotensin II produced by enzymes other than ACE. On the basis of the present clinical trial evidence, AT-1 receptor antagonists, rather than the ACE inhibitors, should be used to treat hypertension associated with left ventricular (LV) hypertrophy. Both groups of drugs are useful when hypertension is not complicated by LV hypertrophy, and in diabetes. In the treatment of diabetes with or without hypertension, there is good clinical support for the use of either an ACE inhibitor or an AT-1 receptor antagonist. ACE inhibitors are recommended in the treatment of renal disease that is not associated with diabetes, after myocardial infarction when left ventricular dysfunction is present, and in heart failure. As the incidence of cough is much lower with the AT-1 receptor antagonists, these can be substituted for ACE inhibitors in patients with hypertension or heart failure who have persistent cough. Preliminary studies suggest that combining an AT-1 receptor antagonist with an ACE inhibitor may be more effective than an ACE inhibitor alone in the treatment of hypertension, diabetes with hypertension, renal disease without diabetes and heart failure. However, further trials are required before combination therapy can be recommended in these conditions.
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PMID:Angiotensin AT-1 receptor antagonism: complementary or alternative to ACE inhibition in cardiovascular and renal disease? 1243 89

Angiotensin-converting enzyme (ACE) inhibitors and more recently angiotensin-receptor blockers (ARBs) have become popular therapies in the end-stage renal disease (ESRD) patient. The ability of either of these drug classes to reduce blood pressure in the ESRD patient is well accepted; however, there is considerably less information available to guide the clinician in the safe and effective use of these drugs in the ESRD patient with congestive heart failure and/or coronary artery disease. Head-to-head studies in the ESRD patient are lacking for both drug classes. Several pharmacokinetic factors can influence the selection of these drugs, including dialysability and the propensity for systemic accumulation. ACE inhibitors (ACE-Is) and ARBs are recognised as having a range of nonpressor effects that are pertinent to patients with ESRD. Such effects include their ability to decrease both thirst drive and erythropoiesis. These drug classes, though, are distinguishable by the unique adverse effect profile for ACE-Is. As is the case in patients without renal failure, ESRD patients can experience cough and, less frequently, angioneurotic oedema with ACE-Is. In the ESRD population, so-called anaphylactoid dialyser reactions can occur in conjunction with ACE-I use. The use of a drug from within the ARB class carries both less risk and permits a compound with a preferred pharmacokinetic profile limited dialysability and minimal systemic accumulation to be administered. These attributes would favour the increased use of ARBs in this population.
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PMID:The pharmacokinetics and pharmacodynamics of angiotensin-receptor blockers in end-stage renal disease. 1258 68

Hypertension remains one of the most unmet medical needs of this century. While many drugs are available for treating hypertension, efforts are still insufficient to find potent therapeutic agents since cause for hypertension in all patients is not the same. Angiotensin-converting enzyme inhibitors (ACEIs) have emerged as an important class of drugs in the treatment of hypertension, congestive heart failure (CHF), protenuric renal disease, myocardial infarction and stroke. This class of drugs blocks the conversion of angiotensin I to angiotensin II and prevents bradykinin breakdown. However, the lack of specificity of ACEIs leads to the frequent side effects like cough and angio-oedema. Recently developed, specific non-peptide and orally active angiotensin receptor blockers (ARBs) have become the prime therapeutics as they alone or co-administration with ACE inhibitors can control the renin angiotensin disorders. This review explores recent developments in the design, synthesis, and structural modifications of ACE inhibitors as well as angiotensin receptor blockers.
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PMID:Advances in angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). 1287 Nov 64

Even well-conducted randomized controlled trials can only reduce uncertainty, not eliminate it. The trials presented in this article all have gaps, and like many studies, some raise more questions than answers. A summary of the current trials, however, can be presented as follows. For patients with essential hypertension who are at high risk for cardiovascular disease, the use of diuretic therapy (excluding simultaneous use of ACE or CCB) resulted in outcomes at least equivalent to the use of either ACE or CCB without diuretics. Naturally, the dilemma for clinicians is that these drugs are most often used in combination with thiazide diuretics, as indicated by the RENAAL trial where 80% of ARB were used with diuretics in patients with type II diabetes and known nephropathy. The increased risk of heart failure observed with ACE and CCB in that trial may be relevant only to patients in whom diuretics were not also used. The study does raise important awareness, however, that ACE or CCB use without diuretic therapy is no better than diuretic therapy, and may be associated with higher risk of certain outcomes. A substantial number of patients with essential hypertension might achieve adequate blood pressure control with diuretic monotherapy. If so, that certainly has important implications for the cost of medical care in this country. For African Americans with essential hypertension, ACE may have advantages as a component of therapy in comparison with CCBs or beta-blockers, although diuretics should probably be the cornerstone of therapy for them and supported by the Seventh Joint National Committee. For patients with proteinuric renal disease, whether associated with diabetes or hypertension, it should be considered inappropriate to use DHP CCB as monotherapy in any setting, whether as part of a clinical trial or in clinical practice. These drugs should not be considered as ethical placebo arms in trials, most especially in diabetic nephropathy, nor should they be used without an ACE or ARB in patients with proteinuric renal disease in the absence of documented contraindications or intolerance to ACE, ARB, or non-DHP CCB (which are now considered second-line agents for proteinuric renal disease, and are acceptable placebo or comparison arms in clinical trials). For patients with type I diabetes, ACE remain the cornerstone of therapy. Because of recent RENAAL and IDNT trial results, the greatest benefit for slowing progression of renal disease in type II diabetic nephropathy now belongs to ARBs. In contrast, however, the HOPE trial showed that ACE, specifically ramipril, had the greatest evidence for prevention of cardiovascular outcomes in patients with renal insufficiency, regardless of diabetic status. Cardiovascular outcomes were secondary end points in the RENAAL and IDNT trials, and with the exception of heart failure for losartan, no benefits on cardiovascular outcomes were statistically significant. Progression of renal disease has only been studied in a relatively small cohort of Israeli patients comparing enalapril with nifedipine. These gaps lead to a classic dilemma in medical decision-making. Because evidence has shown that patients with elevated serum creatinine (greater than or equal to 1.4 mg/dL) are just as likely to die from cardiovascular disease as they are to reach end-stage renal disease, which outcome should be the focus for clinicians, or for researchers? Using a strictly evidence-based approach, this question can only be answered by yet another large, long, randomized, controlled trial. Given the similarity of actions between the ARB and ACE, it is likely there is considerable overlap of both benefits and side-effects between the two, although ARB may have a lower incidence of cough and hyperkalemia. The decision of which antihypertensive agents to use will have to be tailored carefully to the needs of the patient and careful consideration of both medical and economic factors. Regardless of the choice between an ACE or ARB, however, post hoc analysis of clinical trials [21,47] and observational data clearly indicate that patients with chronic kidney disease, even if considered mild (ie, serum creatinine greater than or equal to 1.4 mg/dL) are at significantly greater risk of cardiovascular morbidity and mortality compared with those with better kidney function. As stated in a recent review by the authors of the HOPE trial [50], "the frequent practice of withholding ACE [or ARB] in patients with mild renal insufficiency is unwarranted," because not only are these patients precisely those who might benefit most from their use, but safety and tolerability are generally excellent. Based on the results of the AASK trial, the authors add the same for the use of ACE inhibitors in African Americans.
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PMID:What have we learned from the current trials? 1487 Oct 59

The development of drugs which block the renin-angiotensin system (RAS) has been proven a major advance in cardiovascular medicine. Angiotensin converting enzyme (ACE) inhibitors, which block the formation of angiotensin II from the inactive angiotensin I, are widely used as first line treatment in hypertension, heart failure and diabetic nephropathy. More recently, selective antagonists of the angiotensin type-1 receptor (AT1R) have become available for clinical use. Accumulating evidence suggests that AT1R antagonists have similar effects to ACE inhibitors in hypertension, heart failure and diabetic nephropathy. Although ACE inhibitors and AT1R antagonists block the same system, experimental evidence suggest that their mechanisms of action differ in several respects, such as increased bradykinin and angiotensin 1-7 levels with ACE inhibitors and AT2R activation with AT1R antagonists. Nevertheless, the clinical significance of these differences remains largely unknown and, in practice, the only clear advantage of AT1R antagonists over ACE inhibitors is the absence of cough as a side effect. Recent clinical data suggest that combined ACE inhibition and AT1R antagonism offer additive effects in reducing blood pressure in hypertension, in reducing proteinuria in nephropathy and in improving prognosis in heart failure. Further evidence suggests that some hypertensive patients may have a good antihypertensive response with ACE inhibition but not with AT1R antagonism, or the reverse. These data suggest that these two drug classes have important similarities, because they act on the same system, but they also appear to have important differences, which are not only of theoretical but also of clinical importance.
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PMID:Renin-angiotensin system blockade at the level of the angiotensin converting enzyme or the angiotensin type-1 receptor: similarities and differences. 1496 13

Irbesartan (Avapro, Aprovel) is a potent and selective angiotensin II subtype 1 receptor antagonist indicated for use in patients with hypertension, including those with type 2 diabetes mellitus and nephropathy. Once-daily administration of irbesartan provided 24-hour control of blood pressure (BP). In patients with mild-to-moderate hypertension irbesartan was as effective as enalapril, atenolol and amlodipine, and more effective than valsartan in terms of absolute reduction in BP and response rates. Irbesartan produced a greater reduction in diastolic BP at trough than once-daily losartan, but had a smaller effect than olmesartan; the reduction in systolic BP achieved with irbesartan was similar or greater than that with losartan and similar to that seen with olmesartan. The combination of irbesartan with hydrochlorothiazide produced additive effects on BP reduction. Irbesartan also induced regression of left ventricular mass in patients with hypertension and left ventricular hypertrophy. In two large studies (IRbesartan MicroAlbuminuria type 2 diabetes mellitus in hypertensive patients [IRMA 2] and the Irbesartan Diabetic Nephropathy Trial [IDNT]) irbesartan exerted a renoprotective effect in hypertensive patients with type 2 diabetes at both the early and later stages of diabetic nephropathy. The renoprotective effect was at least partly independent of the BP-lowering effect. In the IRMA 2 trial, the proportion of patients progressing to overt nephropathy was significantly lower for recipients of irbesartan 300mg once daily than placebo. In patients with overt nephropathy in the IDNT, irbesartan 300mg once daily provided significantly greater renoprotection than amlodipine 10mg once daily or placebo. The relative risk of doubling of serum creatinine was significantly lower with irbesartan than amlodipine or placebo. Irbesartan is well tolerated in hypertensive patients, including those with type 2 diabetes and incipient or overt nephropathy. The overall incidence of adverse events with irbesartan was similar to that with placebo. Irbesartan was associated with a lower incidence of cough than enalapril and was not associated with ankle oedema or with any clinically significant drug interactions. In conclusion, irbesartan is a well tolerated and effective antihypertensive agent. It also slows the progression of renal disease in hypertensive patients with type 2 diabetes at both the early and later stages of diabetic nephropathy. Thus, irbesartan is a valuable agent in the management of patients with these indications.
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PMID:Irbesartan: a review of its use in hypertension and in the management of diabetic nephropathy. 1510 93

Dominant mutations in the CIAS1 gene cause a spectrum of autoinflammatory diseases such as familial cold autoinflammatory syndrome, FCAS, which is characterized by episodes of urticaria, arthralgia, fever and conjunctivitis after generalized exposure to cold. We here describe patients of two German families with the 592G-->A, V198M mutation, which has been described to induce FCAS before. However, in our patients the clinical phenotype was very different from this disease. They never had urticaria, cold induced fever or conjunctivitis; instead the following symptoms occurred: Very regular periodic fever, irregular severe febrile episodes, relatively mild arthralgia, dry cough, cardiomyopathy, nephropathy and euthyroid thyroiditis all being reversible. We conclude that the clinical phenotype associated with mutations in the CIAS1 gene is much broader than assumed before.
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PMID:Periodic fever, mild arthralgias, and reversible moderate and severe organ inflammation associated with the V198M mutation in the CIAS1 gene in three German patients--expanding phenotype of CIAS1 related autoinflammatory syndrome. 1524 11

The primary aim of this study was evaluation of the efficacy of telmisartan (angiotensin II receptor blocker- AT(1) blocker) on blood pressure in 10 patients with renal impairment in moderate or advanced stages of renal insufficiency and not dependent on haemodialysis. Its effect on proteinuria, renal function (represented by serum urea, creatinine, glomerular filtration), evaluation of overall therapy compliance in comparison with a previously prescribed angiotensin converting enzyme inhibitors (ACEI) were secondary aims. Considering the presence of left ventricle hypertrophy in all patients as a marker of hypertensive cardiopathy, the effect of telmisartan therapy on non-invasive cardiovascular parameters (ECG, echocardiography, and assessment of heart rate variability-HRV) was also evaluated. The study group involved 10 hypertensive patients (6 women, 4 men) with diabetic and non-diabetic renal impairment, proteinuria above 1 g/24 hours, hypertensive cardiopathy and intolerance of ACEI (cough). Telmisartan was added to their long-term antihypertensive combination therapy in a dose of 40 mg for the first 14 days, after which the dose increased to the maximal of 80 mg. The average initial daytime systolic blood pressure (SBP) was 149 +/- 19.7 mm Hg, average night-time SBP 145 +/- 23.0 mm Hg, average initial daytime diastolic BP (DBP) 90.6 +/- 2.5 mm Hg, night-time DBP 88.9 +/- 13.5 mm Hg. Average initial serum creatinine was 207.2 +/- 48.5 micromol/l, urea 15.1 +/- 4.4 mmol/l, GF 0.5 +/- 0.1 ml/s. Echocardiography revealed left ventricular (LV) hypertrophy with well preserved systolic and moderately impaired diastolic LV function. Also the HRV assessment revealed impaired neurovegetative (e.g. sympathovagal) balance. After 1 year of combination therapy with telmisartan, there was a clearly significant reduction in both SBP and DBP in both day and night-time (SBP daytime 149.6 vs.116.6 mm Hg, night-time 145.8 vs. 129.5 mm Hg; DBP daytime 90.6 vs. 83.5 mm Hg, night-time 88.9 vs. 79.3 mm Hg) and proteinuria (2.37 vs. 1.27 g/24 hour, p < 0.05). There were no significant changes in serum creatinine, urea values, and LV functions. On the other hand, further progression of the sympathovagal balance impairment was noted (continuing reduction of HRV in 9 from 10 patients), which can be described as the priority finding. The total compliance of telmisartan therapy was very good and without adverse clinical side effects. In conclusion - telmisartan reduces blood pressure and proteinuria safely and effectively in patients with various types of nephropathy in moderate or advanced stages of renal insufficiency.
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PMID:Telmisartan in the treatment of hypertension in patients with chronic renal insufficiency. 1552 50


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