In contrast to ACE inhibitors, ARBs permit activation of AT2receptors. ACE inhibitors increase renin release; however, because ACE inhibitors block the conversion of angiotensin I to angiotensin II, ACE inhibition is not associated with increased levels of angiotensin II. ARBs also stimulate renin release; however, with ARBs, this translates into a several-fold increase in circulating levels of angiotensin II. Because AT2 receptors are not blocked by clinically available ARBs, this increased level of angiotensin II is available to activate AT2 receptorsACE inhibitors may increase angiotensin levels more than do ARBs. ACE is involved in the clearance of angiotensin, so inhibition of ACE may increase angiotensin(1-7) levels more so than do ARBs.ACE inhibitors increase the levels of a number of ACE substrates, including bradykinin and Ac-SDKP. ACE is a nondiscriminating enzyme that processes an array of substrates; inhibiting ACE therefore increases the levels of ACE substrates and decreases the levels of their corresponding products. Whether the pharmacological differences between ARBs and ACE inhibitors result in significant differences in therapeutic outcomes is an open question.
The incidence of discontinuation of ARBs owing to adverse reactions is comparable with that of placebo. Unlike ACE inhibitors, ARBs do not cause cough, and the incidence of angioedema with ARBs is much less than with ACE inhibitors. As with ACE inhibitors, ARBs have teratogenic potential and should be discontinued before the second trimester of pregnancy. ARBs should be used cautiously in patients whose arterial blood pressure or renal function is highly dependent on the renin-angiotensin system (e.g., renal artery stenosis). In such patients, ARBs can cause hypotension, oliguria, progressive azotemia, or acute renal failure. ARBs may cause hyperkalemia in patients with renal disease or in patients taking K+ supplements or K+-sparing diuretics. ARBs enhance the blood pressure-lowering effect of other antihypertensive drugs, a desirable effect but one that may necessitate dosage adjustment
Although several types of ARBs are commercially available for the treatment of patients with hypertension, comparisons of the binding affinity to AT1 receptor among them remain to be elucidated. Therefore,the dissociation rate of several ARBs from AT1 receptor was studied in vitro. Angiotensin II time-dependently dissociated telmisartan, olmesartan, candesartan, valsartan, losartan, and an active metabolite of losartan, EXP3174 from membrane components containing human AT1 receptor; with corresponding half-lives (t1/2) of 213, 166, 133, 70, 67, and 81 min, respectively . These results demonstrate that telmisartan could have the strongest binding affinity to AT1 receptor among various ARBs examined here; the rank order of affinity is telmisartan > olmesartan > candesartan > EXP3174 ³ valsartan ³ losartan. Telmisartan may have longlasting blood pressure lowering effects and superior cardioprotective properties in patients with hypertension due to its strongest AT1 receptor antagonistic ability.
Recently, telmisartan was found to act as a partial agonist of peroxisomeproliferator-activated receptor-g (PPAR-g). Furthermore, none of the commercially available ARBs were found not to activate PPAR-g when tested at the concentrations of therapeutic ranges. Telmisartan also induced PPAR-g activity in AT1 receptor-deficient cell models, thus further supporting the concept that telmisartan could stimulate PPAR-g activity independent of its AT1 receptor blocking actions. PPAR-g activity influences the gene expression involved in carbohydrate and lipid metabolism, and pioglitazone and rosiglitazone, ligands for PPAR-g, improve insulin resistance in diabetic patients . Moreover, there is a growing body of evidence that activators of PPAR-g exert antiinflammatory, anti-oxidative and anti-proliferative effects on vascular wall cells, thus decreasing the risks for atherosclerosis [22,23]. These observations suggest that due to its unique PPAR-g-modulating activity, telmisartan may become a promising ‘cardiometabolicsartan’, that targets both diabetes and CVD in hypertensive patients
In vitro, telmisartan augmented glucose transporter isoform 4 expression and 2-deoxy glucose uptake both in basal and insulin-stimulated state of adipocytes . In animal study, telmisartan administration caused a significant attenuation of weight gain and reduced glucose, insulin, and triglyceride levels in rats fed a high-fat, high-carbohydrate diet, compared with treatments of losartan, another type of ARB . Furthermore, recently, some clinical papers also reported the insulin-sensitizing effects of telmisartan inhypertensive patients [26,27].
We have recently found that AT II stimulates intracellular reactive oxygen species (ROS) generation in retinal pericytes through an interaction with type 1 receptor. Further, AT II decreased DNA synthesis and simultaneously up-regulated vascular endothelial growth factor (VEGF) mRNA levels in pericytes, both of which were blocked by treatment with telmisartan or an anti-oxidant, N-acetylcysteine [39, 40]. These results suggest that AT II-type 1 receptor interaction could induce pericyte loss through intracellular ROS generation, thus being involved in diabetic retinopathy, and that telmisartan could be a promising therapeutic strategy for the treatment of early diabetic retinopathy. We have very recently found that AII potentiates the deleterious effects of Advanced Glycation End products on ECs by inducing RAGE protein expression, which was completely blocked by telmisartan . These observations provide the functional interaction between the AGE-RAGE system and the RAS in the pathogenesis of accelerated atherosclerosis in diabetes, thus suggesting a novel beneficial aspect of telmisartan on diabetic vascular complications as well.
BoehringerIngelheim GmbH has recently obtained thepatents of telmisartan for prophylaxis or treatment ofcardiovascular, cardiopulmonary, renal, or insulin resistantdisorders [72,73].Our present findings discussed above suggest thepotential therapeutic implications of telmisartan incardiometabolic disorders. The clinical relevance of thisunique sartan should be further studied in patients withcardiometabolic disorders. To develop novel therapeuticstrategies that specifically target insulin resistance and CVDmay be helpful for most patients with hypertension
Angiotensin Receptor Blockers:TelmisartanThe New Member<br />Dr. Tanoy Bose<br />Post Graduate Trainee<br />Department of Medicine<br />Assam Medical College<br />
Adverse Effects<br />The incidence of discontinuation of ARBs owing to adverse reactions is comparable with that of placebo. <br />Do not cause cough <br />Incidence of angioedema much less <br />Have teratogenic potential : should be discontinued before the second trimester of pregnancy. <br />Cautious in patients whose BP or renal function is highly dependent on RAAS(e.g., renal artery stenosis). <br />May cause hyperkalemia in patients with renal disease or in patients taking K+ supplements or K+-sparing diuretics. <br />Enhance the blood pressure-lowering effect of other antihypertensive drugs.<br />
Telmisartan: Pharmacology<br />Peak plasma levels are obtained approximately 0.5 to 1 hour after oral administration<br /> Plasma t 1/2≈ 24 hours. <br />Cleared from the circulation mainly by biliary secretion of intact drug. <br />Clearance affected by hepatic but not renal insufficiency. <br />The recommended oral dosage : 40 to 80 mg once daily<br />
Role in Diabetic Complications ?</li></li></ul><li>Why Telmisartan?Pharmacologic superiority!!<br />Binding affinity of ARB to AT1 receptor<br />Telmi> Olme> Cande> Valsar> Losar<br />Kakuta H, Sudoh K, Sasamatsu M, Yamagishi S. Telmisartan has the strongest binding affinity to angiotensin II type 1 receptor. Comparison with other angiotensin II type 1 receptor blockers. Int J ClinPharm Res (in press).<br /><ul><li>Could have strongest affinity to AT1
May become a promising ‘cardiometabolicsartan’, that targets both diabetes and CVD in hypertensive patients</li></li></ul><li>Why Telmisartan?Insulin sensitiser!!<br />In vitro : Augmented glucose transporter isoform 4 expression and 2-deoxy glucose uptake both in basal and insulin-stimulated state of adipocytes.<br />Fujimoto M, Masuzaki H, Tanaka T, et al . An angiotensin II AT1 receptor antagonist, telmisartan augments glucose uptake and GLUT4 protein expression in 3T3L-1 adipocytes. FEBS Lett 2004; 576: 492-7<br />In animal study : Significant attenuation of weight gain and reduced glucose, insulin, and triglyceride levels in rats fed a high-fat, high-carbohydrate diet, compared with treatments of losartan, another type of ARB .<br />Benson SC, Pershadsingh HA, Ho CI, et al. Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPAR gamma-modulating activity. Hypertension 2004; 43: 993-1002<br />Some recent papers: Insulin-sensitizing effects of telmisartan in hypertensive patients<br />Miura Y, Yamamoto N, Tsunekawa S, et al. Replacement of valsartan and candesartan by telmisartan in hypertensive patients with diabetes. Diabetes Care 2005; 28, 757-8.<br />
Why Telmisartan?Diabetic complications!!<br />Blockade of upregulation of VEGF mRNA & destimulation of ROS in retinal pericytes : Promising Rx strategy for early Rx of DM retinopathy<br />Yamagishi S, Amano S, Inagaki Y, et al. Angiotensin II-type 1 receptor interaction upregulates vascular endothelial growth factor messenger RNA levels in retinal pericytes through intracellular reactive oxygen species generation. Drugs Exp Clin Res 2003; 29: 75-80.<br /><ul><li>Complete Blockade of Receptor –AGE (RAGE) protein expression in Retinal endothelial cells : Novel beneficial effect on Diabetic vascular complications</li></ul>Yamagishi S, Takeuchi M, Matsui T, et al. Angiotensin II augments advanced glycation end product-induced pericyte apoptosis through RAGE overexpression. FEBS Lett (DOI: 10.1016/j.febslet. 2005.06.058).<br />
To Conclude<br />The experimental animal as well as hypothetical models need to be reinforced by well conducted multicentricrandomised trials.<br />The aforementioned actions and probable advantages bear a high risk of getting derecognised in human trials.<br />Needless to mention that a unique future lies with this drug considering its pleiotropism especially when the management of diabetes and related complication is in question.<br />