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07-SEPTEMBER-2008 03:17:44 - Angiotensin II receptor antagonist Losartan, the first ARB Losartan, the first ARB Angiotensin II receptor antagonists, also known as angiotensin receptor blockers ARBs, AT1-receptor antagonists or sartans, are a group of pharmaceuticals which modulate the renin-angiotensin-aldosterone system. Their main use is in hypertension high blood pressure, diabetic nephropathy kidney damage due to diabetes and congestive heart failure. In 2008 they were reported to have a remarkable negative association with Alzheimer's Disease. A retrospective analysis of five million patient records with the US Department of Veterans Affairs system found that different types of commonly used anti-hypertensive medications had very different AD outcomes. Those patients taking angiotensin receptor blockers ARBs were 35-40% less likely to develop AD than those using other anti-hypertensives. 1 Contents 1 Mode of action 2 Uses 3 Adverse effects 3.1 Myocardial Infarction: the controversy 4 References Mode of action These substances are AT1-receptor antagonists - that is, they block the activation of angiotensin II AT1 receptors. Blockade of AT1 receptors directly causes vasodilation, reduces secretion of vasopressin, reduces production and secretion of aldosterone, amongst other actions - the combined effect of which is reduction of blood pressure. The specific efficacy of each ARB within this class is made up of a combination of three pharmacodynamic and pharmacokinetic parameters. These areas are: 1 Pressor inhibition at trough or the 24th hour this clinically important measurement relates to the amount of blockade or inhibition of the BP raising effect of angiotension II. The rates as listed in the US FDA Package Inserts for inhibition of this effect at the 24th hour for the ARBs are as follows: all doses listed in PI are included Valsartan 80mg 30% Telmisartan 80mg 40% Losartan 100mg 25- 40% Irbesartan 150mg 40% Irbesartan 300mg 60% Olmesartan 20mg 61% Olmesartan 40mg 74% 2 AT1 affinity, AT1 affinity vs AT2 is the second meaningful area out of three that make up the efficacy of an individual ARB. The specific AT1 affinity relates to how specificially attracted the medicine is for the correct receptor, the US FDA Package Insert rates for AT1 affinity are as follows: Losartan 1000 fold Telmisartan 3000 fold Irbesartan 8500 fold Olmesartan 12500 fold Valsartan 20000 fold 3 The third area that completes the overall efficacy picture of an ARB is its biological half life. The rates from the US FDA Package Inserts are as follows: Valsartan 6 Losartan 6- 9 Irbesartan 11- 15 Olmesartan 13 Telmisartan 24 Based on the above data for the three key PD/ PK areas that indicate efficacy it is important to see that you need a combination of all three at an effective level. Uses Angiotensin II receptor antagonists are primarily used for the treatment of hypertension where the patient is intolerant of ACE inhibitor therapy. They do not inhibit the breakdown of bradykinin or other kinins, and are thus only rarely associated with the persistent dry cough and/or angioedema that limit ACE inhibitor therapy. More recently, they have been used for the treatment of heart failure in patients intolerant of ACE inhibitor therapy, particularly candesartan. Irbesartan and losartan have trial data showing benefit in hypertensive patients with type II diabetes, and may delay the progression of diabetic nephropathy. Candesartan is used experimentally in preventive treatment of migraine.2 Another angiotensin II receptor antagonist, olmesartan, is an important part of the Marshall Protocol, invented by American biomedical researcher Trevor Marshall. The angiotensin II receptor blockers have differing potencies in relation to blood pressure control, with statistically differing blood pressure effects at the maximal doses.3 When used in clinical practice, the particular agent used may vary based on the degree of blood pressure response required. Adverse effects This class of drugs is usually well-tolerated, with common adverse drug reactions ADRs including: dizziness, headache, and/or hyperkalemia. Infrequent ADRs associated with therapy include: first dose orthostatic hypotension, rash, diarrhea, dyspepsia, abnormal liver function, muscle cramp, myalgia, back pain, insomnia, decreased haemoglobin levels, renal impairment, pharyngitis, and/or nasal congestion. Rossi, 2006 While one of the main rationales for the use of this class is the avoidance of dry cough and/or angioedema associated with ACE inhibitor therapy, they may still rarely occur. Additionally, there is also a small risk of cross-reactivity in patients who have experienced angioedema with ACE inhibitor therapy. Rossi, 2006 Myocardial Infarction: the controversy Whether Angiotensin II Receptor Blockers may increase or not the risk of Myocardial Infarction was announced in the BMJ,4 and was more recently debated in the medical journal of the American Heart Association: Circulation.56 To date, there is no consensus on whether ARBs have a tendency to increase MI, but there is also no substantive evidence to indicate that ARBs are able to reduce MI. In the VALUE trial, the angiotensin II receptor blocker Valsartan produced a statistically significant 19% p=0.02 relative increase in the prespecified secondary end point of myocardial infarction fatal and non-fatal compared with amlodipine.7 The CHARM-alternative trial showed a significant +52% p=0.025 increase in myocardial infarction with candesartan versus placebo despite a reduction in blood pressure.8 Indeed, as a consequence of AT1 blockade, ARBs increase Angiotensin II levels several-fold above baseline by uncoupling a negative-feedback loop. Increased levels of circulating Angiotensin II result in unopposed stimulation of the AT2 receptors, which are, in addition upregulated. Unfortunately, recent data suggest that AT2 receptor stimulation may be less beneficial than previously proposed and may even be harmful under certain circumstances through mediation of growth promotion, fibrosis, and hypertrophy , as well as proatherogenic and proinflammatory effects.91011 References ^ Angiotensin receptor blockers are lower incidence, progression of Alzheimer's disease ^ Tronvik E, Stovner LJ, Helde G, Sand T, Bovim G. 2003. Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomized controlled trial. JAMA 1 289 Pt 1: 65-9. doi:10.1001/jama.289.1.65. PMID 12503978. ^ Kassler-Taub K, Littlejohn T, Elliott W, Ruddy T, Adler E. 1998. Comparative efficacy of two angiotensin II receptor antagonists, irbesartan and losartan in mild-to-moderate hypertension. Irbesartan/Losartan Study Investigators. Am J Hypertens 11 4 Pt 1: 445-53. doi:10.1016/S0895-70619700491-3. PMID 9607383. ^ Verma S, Strauss M 2004. Angiotensin receptor blockers and myocardial infarction. BMJ 329 7477: 1248-9. doi:10.1136/bmj.329.7477.1248. PMID 15564232. ^ Strauss MH, Hall AS 2006. Angiotensin receptor blockers may increase risk of myocardial infarction: unraveling the ARB-MI paradox. Circulation 114 8: 838-54. doi:10.1161/CIRCULATIONAHA.105.594986. PMID 16923768. ^ Tsuyuki RT, McDonald MA 2006. Angiotensin receptor blockers do not increase risk of myocardial infarction. Circulation 114 8: 855-60. doi:10.1161/CIRCULATIONAHA.105.594978. PMID 16923769. ^ Julius S, Kjeldsen SE, Weber M, et al 2004. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 363 9426: 2022-31. doi:10.1016/S0140-67360416451-9. PMID 15207952. ^ Granger CB, McMurray JJ, Yusuf S, et al 2003. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet 362 9386: 772-6. doi:10.1016/S0140-67360314284-5. PMID 13678870. ^ Levy BI 2005. How to explain the differences between renin angiotensin system modulators. Am. J. Hypertens. 18 9 Pt 2: 134S-141S. doi:10.1016/j.amjhyper.2005.05.005. PMID 16125050. ^ Lévy BI 2004. Can angiotensin II type 2 receptors have deleterious effects in cardiovascular disease? Implications for therapeutic blockade of the renin-angiotensin system. Circulation 109 1: 8-13. doi:10.1161/01.CIR.0000096609.73772.C5. PMID 14707017. ^ Reudelhuber TL 2005. The continuing saga of the AT2 receptor: a case of the good, the bad, and the innocuous. Hypertension 46 6: 1261-2. doi:10.1161/01.HYP.0000193498.07087.83. PMID 16286568. Rossi S, or. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. v d e Major drug groups Gastrointestinal tract/metabolism A stomach acid Antacids, H2 antagonists, Proton pump inhibitors Antiemetics Laxatives Antidiarrhoeals/Antipropulsives Anti-obesity drugs Anti-diabetics Vitamins Dietary minerals Blood and blood forming organs B Antithrombotics Anticoagulants, Antiplatelets, Thrombolytics Antihemorrhagics Cardiovascular system C cardiac therapy/antianginals Cardiac glycosides, Antiarrhythmics, Cardiac stimulant Antihypertensives Diuretics Vasodilators Beta blockers renin-angiotensin system ACE inhibitors, Angiotensin II receptor antagonists, Renin inhibitors Antihyperlipidemics Skin D Emollients Cicatrizant Antipruritics Reproductive system G Hormonal contraception Fertility agents SERMs Sex hormones Endocrine system H Corticosteroids Sex hormones Thyroid hormones Antithyroid agent Infections and infestations J, P Antibiotics Antivirals Vaccines Antifungals Antiparasitic Antiprotozoals, Anthelmintics Malignant and immune disease L Anticancer agents Immunostimulators Immunosuppressants Muscles, bones, and joints M Anabolic steroids Anti-inflammatories NSAID Antirheumatics Corticosteroids Muscle relaxants Brain and nervous system N Anesthetics General, Local Analgesics Anticonvulsants Mood stabilizers Psycholeptic Anxiolytics, Antipsychotics, Hypnotics/Sedatives Psychoanaleptic Antidepressants, Stimulants/Psychostimulants Respiratory system R Bronchodilators Decongestants H1 antagonists Other ATC V Antidotes Contrast media Radiopharmaceuticals Dressing v d e Agents acting on the renin-angiotensin system C09 ACE inhibitors Alacepril Benazepril Captopril Cilazapril Delapril Enalapril Fosinopril Imidapril Lisinopril Moexipril Perindopril Quinapril Ramipril Rentiapril Spirapril Temocapril Trandolapril Zofenopril Angiotensin II receptor antagonists AIIRA Azilsartan Candesartan Eprosartan Irbesartan Losartan Olmesartan Tasosartan Telmisartan Valsartan Renin inhibitors Aliskiren Remikiren Retrieved from http://en..org/wiki/Angiotensin_II_receptor_antagonist Categories: Angiotensin II receptor antagonists Views Article Discussion this page History Personal tools Log in / create account Navigation Main page Contents Featured content Current events Random article Search Go Search Interaction Community portal Recent changes Contact Donate to Help Toolbox What links here Related changes Upload file Special pages Printable version Permanent link Cite this page Languages Türkçe Deutsch Español Français Nederlands 日本語 Polski Português ไทย This page was last modified on 18 August 2008, at 02:30
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