Angiotensin II receptor blocker


Angiotensin II receptor blockers, formally angiotensin II receptor type 1 antagonists, also known as angiotensin receptor blockers, angiotensin II receptor antagonists, or AT1 receptor antagonists, are a group of pharmaceuticals that bind to and inhibit the angiotensin II receptor type 1 and thereby block the arteriolar contraction and sodium retention effects of renin–angiotensin system.
Their main uses are in the treatment of hypertension, diabetic nephropathy and congestive heart failure. They selectively block the activation of the AT1 receptor, preventing the binding of angiotensin II compared to ACE inhibitors.
ARBs and the similar-attributed ACE inhibitors are both indicated as the first-line antihypertensives in patients developing hypertension along with left-sided heart failure. However, ARBs appear to produce fewer adverse effects compared to ACE inhibitors.

Medical uses

Angiotensin II receptor blockers are used primarily for the treatment of hypertension where the patient is intolerant of ACE inhibitor therapy primarily because of persistent and/or dry cough. 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, in particular candesartan. Irbesartan and losartan have trial data showing benefit in hypertensive patients with type 2 diabetes, and may delay the progression of diabetic nephropathy. A 1998 double-blind study found "that lisinopril improved insulin sensitivity whereas losartan did not affect it." Candesartan is used experimentally in preventive treatment of migraine. Lisinopril has been found less often effective than candesartan at preventing migraine.
The angiotensin II receptor blockers have differing potencies in relation to blood pressure control, with statistically differing effects at the maximal doses. When used in clinical practice, the particular agent used may vary based on the degree of response required.
Some of these drugs have a uricosuric effect.
Angiotensin II, through AT1 receptor stimulation, is a major stress hormone and, because block these receptors, in addition to their eliciting anti-hypertensive effects, may be considered for the treatment of stress-related disorders.
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 different types of commonly used antihypertensive medications had very different AD outcomes. Those patients taking angiotensin receptor blockers were 35 to 40% less likely to develop AD than those using other antihypertensives.
A retrospective study of 1,968 stroke patients revealed that prestroke treatment with ARB may be associated with both reduced stroke severity and better outcome. This finding agrees with experimental data that suggest that ARB's exert a cerebral protective effect.

Adverse effects

This class of drugs is usually well tolerated. Common adverse drug reactions include: 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 hemoglobin levels, renal impairment, pharyngitis, and/or nasal congestion. A 2014 Cochrane systematic review based on randomized controlled trials reported that when comparing patients taking ACE inhibitors to patients taking ARBs, fewer ARB patients withdrew from the study due to adverse events compared to ACE inhibitor patients.
While one of the main rationales for the use of this class is the avoidance of a persistent dry cough and/or angioedema associated with ACE inhibitor therapy, rarely they may still occur. In addition, there is also a small risk of cross-reactivity in patients having experienced angioedema with ACE inhibitor therapy.

Myocardial infarction

The issue of whether angiotensin II receptor antagonists slightly increase the risk of myocardial infarction is currently being investigated. Some studies suggest ARBs can increase the risk of MI. However, other studies have found ARBs do not increase the risk of MI. To date, with no consensus on whether ARBs have a tendency to increase the risk of myocardial infarction, further investigations are underway.
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. However, recent data suggest 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 eliciting proatherogenic and proinflammatory effects.

Cancer

A study published in 2010 determined that "...meta-analysis of randomised controlled trials suggests that ARBs are associated with a modestly increased risk of new cancer diagnosis. Given the limited data, it is not possible to draw conclusions about the exact risk of cancer associated with each particular drug. These findings warrant further investigation." A later meta-analysis by the U.S. Food and Drug Administration of 31 randomized controlled trials comparing ARBs to other treatment found no evidence of an increased risk of incident cancer, cancer-related death, breast cancer, lung cancer, or prostate cancer in patients receiving ARBs. In 2013, comparative effectiveness research from the United States Department of Veterans Affairs on the experience of more than a million veterans found no increased risks for either lung cancer or prostate cancer. The researchers concluded: "In this large nationwide cohort of United States Veterans, we found no evidence to support any concern of increased risk of lung cancer among new users of ARBs compared with nonusers. Our findings were consistent with a protective effect of ARBs."
In May 2013, a senior regulator at the Food & Drug Administration, Medical Team Leader Thomas A. Marciniak, revealed publicly that contrary to the FDA's official conclusion that there was no increased cancer risk, after a patient-by-patient examination of the available FDA data he had concluded that there was a lung-cancer risk increase of about 24% in ARB patients, compared with patients taking a placebo or other drugs. One of the criticisms Marciniak made was that the earlier FDA meta-analysis did not count lung carcinomas as cancers. In ten of the eleven studies he examined, Marciniak said that there were more lung cancer cases in the ARB group than the control group. Ellis Unger, chief of the drug-evaluation division that includes Marciniak, was quoted as calling the complaints a "diversion," and saying in an interview, "We have no reason to tell the public anything new." In an article about the dispute, the Wall Street Journal interviewed three other doctors to get their views; one had "no doubt" ARBs increased cancer risk, one was concerned and wanted to see more data, and the third thought there was either no relationship or a hard to detect, low-frequency relationship.
A 2016 meta-analysis including 148,334 patients found no significant differences in cancer incidence associated with ARB use.

Kidney failure

Although ARBs have protective effects against developing kidney diseases for patients with diabetes and previous hypertension without administration of ARBs, ARBs may worsen kidney functions such as reducing glomerular filtration rate associated with a rise of serum creatinine in patients with pre-existing proteinuria, renal artery stenosis, hypertensive nephrosclerosis, heart failure, polycystic kidney disease, chronic kidney disease, interstitial fibrosis, focal segmental glomerulosclerosis, or any conditions such as ARBs-treated but still clinically present hypertension that lead to abnormal narrowing of blood vessels to the kidney that interrupts oxygen and nutrient supply to the organ.

History

Structure

, irbesartan, olmesartan, candesartan, valsartan, fimasartan include the tetrazole group. Losartan, irbesartan, olmesartan, candesartan, and telmisartan include one or two imidazole groups.

Mechanism of action

These substances are AT1-receptor antagonists; that is, they block the activation of angiotensin II AT1 receptors. AT1 receptors are found in smooth muscle cells of vessels, cortical cells of the adrenal gland, and adrenergic nerve synapses. Blockage of AT1 receptors directly causes vasodilation, reduces secretion of vasopressin, and reduces production and secretion of aldosterone, among other actions. The combined effect reduces blood pressure.
The specific efficacy of each ARB within this class depends upon a combination of three pharmacodynamic and pharmacokinetic parameters. Efficacy requires three key PD/PK areas at an effective level; the parameters of the three characteristics will need to be compiled into a table similar to one below, eliminating duplications and arriving at consensus values; the latter are at variance now.

Pressor inhibition

inhibition at trough level this relates to the degree of blockade or inhibition of the blood pressure-raising effect of angiotensin II. However, pressor inhibition is not a measure of blood pressure-lowering efficacy per se. The rates as listed in the U.S. Food and Drug Administration Package Inserts for inhibition of this effect at the 24th hour for the ARBs are as follows: