Angiotensin II receptor antagonist
Encyclopedia
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
(high blood pressure), diabetic nephropathy
Diabetic nephropathy
Diabetic nephropathy , also known as Kimmelstiel-Wilson syndrome, or nodular diabetic glomerulosclerosis and intercapillary glomerulonephritis, is a progressive kidney disease caused by angiopathy of capillaries in the kidney glomeruli. It is characterized by nephrotic syndrome and diffuse...
(kidney damage due to diabetes
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
) and congestive heart failure
Congestive heart failure
Heart failure often called congestive heart failure is generally defined as the inability of the heart to supply sufficient blood flow to meet the needs of the body. Heart failure can cause a number of symptoms including shortness of breath, leg swelling, and exercise intolerance. The condition...
.
Structure
LosartanLosartan
Losartan is an angiotensin II receptor antagonist drug used mainly to treat high blood pressure . Losartan was the first angiotensin II receptor antagonist to be marketed. Losartan potassium is marketed by Merck & Co. Inc. under the trade name Cozaar...
, irbesartan
Irbesartan
Irbesartan is an angiotensin II receptor antagonist used mainly for the treatment of hypertension. Irbesartan was developed by Sanofi Research...
, olmesartan
Olmesartan
Olmesartan medoxomil is an angiotensin II receptor antagonist used to treat high blood pressure.-Indications:...
, candesartan
Candesartan
Candesartan is an angiotensin II receptor antagonist used mainly for the treatment of hypertension. The prodrug candesartan cilexetil is marketed by AstraZeneca and Takeda Pharmaceuticals, commonly under the trade names Blopress, Atacand, Amias, and Ratacand.-Clinical use:As all angiotensin II...
and valsartan
Valsartan
Valsartan is an angiotensin II receptor antagonist , with particularly high affinity for the type I angiotensin receptor. By blocking the action of angiotensin, valsartan dilates blood vessels and reduces blood pressure...
include the tetrazole
Tetrazole
Tetrazoles are a class of synthetic organic heterocyclic compound, consisting of a 5-member ring of four nitrogen and one carbon atom . The simplest is tetrazole itself, CN4H2. They are unknown in nature...
group (a ring with four nitrogen and one carbon).
Losartan, irbesartan, olmesartan, candesartan, and telmisartan
Telmisartan
Telmisartan is an angiotensin II receptor antagonist used in the management of hypertension. It is marketed under the trade name Micardis , among others.-Administration:...
include one or two imidazole
Imidazole
Imidazole is an organic compound with the formula C3H4N2. This aromatic heterocyclic is a diazole and is classified as an alkaloid. Imidazole refers to the parent compound, whereas imidazoles are a class of heterocycles with similar ring structure, but varying substituents...
groups.
Mechanism of action
These substances are AT1-receptor antagonists – that is, they block the activation of angiotensin II AT1 receptorsAngiotensin receptor
The angiotensin receptors are a class of G protein-coupled receptors with angiotensin II as their ligands. They are important in the renin-angiotensin system: they are responsible for the signal transduction of the vasoconstricting stimulus of the main effector hormone, angiotensin...
. Blockade of AT1 receptors directly causes vasodilation
Vasodilation
Vasodilation refers to the widening of blood vessels resulting from relaxation of smooth muscle cells within the vessel walls, particularly in the large arteries, smaller arterioles and large veins. The process is essentially the opposite of vasoconstriction, or the narrowing of blood vessels. When...
, reduces secretion of vasopressin
Vasopressin
Arginine vasopressin , also known as vasopressin, argipressin or antidiuretic hormone , is a neurohypophysial hormone found in most mammals, including humans. Vasopressin is a peptide hormone that controls the reabsorption of molecules in the tubules of the kidneys by affecting the tissue's...
, and reduces production and secretion of aldosterone
Aldosterone
Aldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that...
, amongst 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
Pressor inhibition at trough level - this relates to the degree of blockade or inhibition of the blood pressure-raising ("pressor") effect of angiotensin II. However, pressor inhibition is not a measure of blood pressure-lowering (BP) efficacy per se. The rates as listed in the US FDA Package Inserts (PIs) for inhibition of this effect at the 24th hour for the ARBs are as follows: (all doses listed in PI are included)- ValsartanValsartanValsartan is an angiotensin II receptor antagonist , with particularly high affinity for the type I angiotensin receptor. By blocking the action of angiotensin, valsartan dilates blood vessels and reduces blood pressure...
80 mg 30% - TelmisartanTelmisartanTelmisartan is an angiotensin II receptor antagonist used in the management of hypertension. It is marketed under the trade name Micardis , among others.-Administration:...
80 mg 40% - LosartanLosartanLosartan is an angiotensin II receptor antagonist drug used mainly to treat high blood pressure . Losartan was the first angiotensin II receptor antagonist to be marketed. Losartan potassium is marketed by Merck & Co. Inc. under the trade name Cozaar...
100 mg 25–40% - IrbesartanIrbesartanIrbesartan is an angiotensin II receptor antagonist used mainly for the treatment of hypertension. Irbesartan was developed by Sanofi Research...
150 mg 40% - Irbesartan 300 mg 60%
- AzilsartanAzilsartanAzilsartan is an angiotensin II receptor antagonist used in the treatment of hypertension that was developed by Takeda....
32 mg 60% - OlmesartanOlmesartanOlmesartan medoxomil is an angiotensin II receptor antagonist used to treat high blood pressure.-Indications:...
20 mg 61% - Olmesartan 40 mg 74%
AT1 affinity
AT1 affinity vs AT2 is not a meaningful efficacy measurement of BP response.The specific AT1 affinity relates to how specifically attracted the medicine is for the correct receptor, the US FDA PI rates for AT1 affinity are as follows:
- LosartanLosartanLosartan is an angiotensin II receptor antagonist drug used mainly to treat high blood pressure . Losartan was the first angiotensin II receptor antagonist to be marketed. Losartan potassium is marketed by Merck & Co. Inc. under the trade name Cozaar...
1000 fold - TelmisartanTelmisartanTelmisartan is an angiotensin II receptor antagonist used in the management of hypertension. It is marketed under the trade name Micardis , among others.-Administration:...
3000 fold - IrbesartanIrbesartanIrbesartan is an angiotensin II receptor antagonist used mainly for the treatment of hypertension. Irbesartan was developed by Sanofi Research...
8500 fold - AzilsartanAzilsartanAzilsartan is an angiotensin II receptor antagonist used in the treatment of hypertension that was developed by Takeda....
greater than 10000 fold - OlmesartanOlmesartanOlmesartan medoxomil is an angiotensin II receptor antagonist used to treat high blood pressure.-Indications:...
12500 fold - ValsartanValsartanValsartan is an angiotensin II receptor antagonist , with particularly high affinity for the type I angiotensin receptor. By blocking the action of angiotensin, valsartan dilates blood vessels and reduces blood pressure...
20000 fold
Biological half-life
The third area needed to complete the overall efficacy picture of an ARB is its biological half-lifeBiological half-life
The biological half-life or elimination half-life of a substance is the time it takes for a substance to lose half of its pharmacologic, physiologic, or radiologic activity, as per the MeSH definition...
. The half-lives from the US FDA PIs are as follows:
- ValsartanValsartanValsartan is an angiotensin II receptor antagonist , with particularly high affinity for the type I angiotensin receptor. By blocking the action of angiotensin, valsartan dilates blood vessels and reduces blood pressure...
6 hours - LosartanLosartanLosartan is an angiotensin II receptor antagonist drug used mainly to treat high blood pressure . Losartan was the first angiotensin II receptor antagonist to be marketed. Losartan potassium is marketed by Merck & Co. Inc. under the trade name Cozaar...
6–9 hours - AzilsartanAzilsartanAzilsartan is an angiotensin II receptor antagonist used in the treatment of hypertension that was developed by Takeda....
11 hours - IrbesartanIrbesartanIrbesartan is an angiotensin II receptor antagonist used mainly for the treatment of hypertension. Irbesartan was developed by Sanofi Research...
11–15 hours - OlmesartanOlmesartanOlmesartan medoxomil is an angiotensin II receptor antagonist used to treat high blood pressure.-Indications:...
13 hours - TelmisartanTelmisartanTelmisartan is an angiotensin II receptor antagonist used in the management of hypertension. It is marketed under the trade name Micardis , among others.-Administration:...
24 hours
Drug comparison and pharmacokinetics
| Drug | Trade Name | Biological half-life [h] | Protein binding [%] | Bioavailability [%] | Renal/hepatic clearance Clearance (medicine) In medicine, the clearance is a measurement of the renal excretion ability. Although clearance may also involve other organs than the kidney, it is almost synonymous with renal clearance or renal plasma clearance. Each substance has a specific clearance that depends on its filtration characteristics... [%] |
Food effect | Daily dosage [mg] |
|---|---|---|---|---|---|---|---|
| Losartan Losartan Losartan is an angiotensin II receptor antagonist drug used mainly to treat high blood pressure . Losartan was the first angiotensin II receptor antagonist to be marketed. Losartan potassium is marketed by Merck & Co. Inc. under the trade name Cozaar... |
Cozaar | 2 h | 98.7% | 33% | 10%/90% | Minimal | 50–100 mg |
| EXP 3174 | 6–9 h | 99.8% | – | 50%/50% | – | – | |
| Candesartan Candesartan Candesartan is an angiotensin II receptor antagonist used mainly for the treatment of hypertension. The prodrug candesartan cilexetil is marketed by AstraZeneca and Takeda Pharmaceuticals, commonly under the trade names Blopress, Atacand, Amias, and Ratacand.-Clinical use:As all angiotensin II... |
Atacand | 9h | >99% | 15% | 60%/40% | No | 4–32 mg |
| Valsartan Valsartan Valsartan is an angiotensin II receptor antagonist , with particularly high affinity for the type I angiotensin receptor. By blocking the action of angiotensin, valsartan dilates blood vessels and reduces blood pressure... |
Diovan | 6 h | 95% | 25% | 30%/70% | No | 80–320 mg |
| Irbesartan Irbesartan Irbesartan is an angiotensin II receptor antagonist used mainly for the treatment of hypertension. Irbesartan was developed by Sanofi Research... |
Avapro | 11–15 h | 90–95% | 70% | 1%/99% | No | 150–300 mg |
| Telmisartan Telmisartan Telmisartan is an angiotensin II receptor antagonist used in the management of hypertension. It is marketed under the trade name Micardis , among others.-Administration:... |
Micardis | 24 h | >99% | 42–58% | 1%/99% | No | 40–80 mg |
| Eprosartan Eprosartan Eprosartan is an angiotensin II receptor antagonist used for the treatment of high blood pressure. It is marketed as Teveten by Abbott Laboratories in the United States.It is marketed as Eprozar by INTAS Pharmaceuticals in the INDIA and by Solvay Pharmaceuticals elsewhere... |
Teveten | 5 h | 98% | 13% | 30%/70% | No | 400–800 mg |
| Olmesartan Olmesartan Olmesartan medoxomil is an angiotensin II receptor antagonist used to treat high blood pressure.-Indications:... |
Benicar | 14–16 h | >99% | 29% | 40%/60% | No | 10–40 mg |
| Azilsartan Azilsartan Azilsartan is an angiotensin II receptor antagonist used in the treatment of hypertension that was developed by Takeda.... |
Edarbi | 11 h | >99% | 60% | 55%/42% | No | 40–80 mg |
Uses
Angiotensin II receptor antagonists are primarily used for the treatment of hypertensionHypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
where the patient is intolerant of ACE inhibitor
ACE inhibitor
ACE inhibitors or angiotensin-converting enzyme inhibitors are a group of drugs used primarily for the treatment of hypertension and congestive heart failure...
therapy. They do not inhibit the breakdown of bradykinin
Bradykinin
Bradykinin is a peptide that causes blood vessels to dilate , and therefore causes blood pressure to lower. A class of drugs called ACE inhibitors, which are used to lower blood pressure, increase bradykinin further lowering blood pressure...
or other kinin
Kinin
A kinin is any of various structurally related polypeptides, such as bradykinin and kallikrein. They are members of the autacoid family.They act locally to induce vasodilation and contraction of smooth muscle.It is a component of the kinin-kallikrein system....
s, and are thus only rarely associated with the persistent dry cough and/or angioedema
Angioedema
Angioedema or Quincke's edema is the rapid swelling of the dermis, subcutaneous tissue, mucosa and submucosal tissues. It is very similar to urticaria, but urticaria, commonly known as hives, occurs in the upper dermis...
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
Candesartan
Candesartan is an angiotensin II receptor antagonist used mainly for the treatment of hypertension. The prodrug candesartan cilexetil is marketed by AstraZeneca and Takeda Pharmaceuticals, commonly under the trade names Blopress, Atacand, Amias, and Ratacand.-Clinical use:As all angiotensin II...
. Irbesartan and losartan have trial data showing benefit in hypertensive patients with type II diabetes, and may delay the progression of diabetic nephropathy
Diabetic nephropathy
Diabetic nephropathy , also known as Kimmelstiel-Wilson syndrome, or nodular diabetic glomerulosclerosis and intercapillary glomerulonephritis, is a progressive kidney disease caused by angiopathy of capillaries in the kidney glomeruli. It is characterized by nephrotic syndrome and diffuse...
. Candesartan
Candesartan
Candesartan is an angiotensin II receptor antagonist used mainly for the treatment of hypertension. The prodrug candesartan cilexetil is marketed by AstraZeneca and Takeda Pharmaceuticals, commonly under the trade names Blopress, Atacand, Amias, and Ratacand.-Clinical use:As all angiotensin II...
is used experimentally in preventive treatment of migraine.
The angiotensin II receptor blockers have differing potencies in relation to BP control, with statistically differing BP 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
Uricosuric
Uricosuric medications are substances that increase the excretion of uric acid in the urine, thus reducing the concentration of uric acid in blood plasma. In general, this effect is achieved by action on the proximal tubule...
effect.
In 2008, they were reported to have a remarkable negative association with Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
(AD). A retrospective analysis of five million patient records with the US Department of Veterans Affairs
United States Department of Veterans Affairs
The United States Department of Veterans Affairs is a government-run military veteran benefit system with Cabinet-level status. It is the United States government’s second largest department, after the United States Department of Defense...
system found different types of commonly used antihypertensive 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 antihypertensives.
Adverse effects
This class of drugs is usually well-tolerated. Common adverse drug reactionAdverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
s (ADRs) include: dizziness, headache, and/or hyperkalemia
Hyperkalemia
Hyperkalemia refers to the condition in which the concentration of the electrolyte potassium in the blood is elevated...
. Infrequent ADRs associated with therapy include: first dose orthostatic hypotension
Orthostatic hypotension
Orthostatic hypotension, also known as postural hypotension, orthostasis, and colloquially as head rush or dizzy spell, is a form of hypotension in which a person's blood pressure suddenly falls when the person stands up or stretches. The decrease is typically greater than 20/10 mm Hg, and may be...
, rash, diarrhea, dyspepsia
Dyspepsia
Dyspepsia , also known as upset stomach or indigestion, refers to a condition of impaired digestion. It is a medical condition characterized by chronic or recurrent pain in the upper abdomen, upper abdominal fullness and feeling full earlier than expected when eating...
, abnormal liver function, muscle cramp, myalgia
Myalgia
Myalgia means "muscle pain" and is a symptom of many diseases and disorders. The most common causes are the overuse or over-stretching of a muscle or group of muscles. Myalgia without a traumatic history is often due to viral infections...
, back pain, insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, decreased hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
levels, renal impairment, pharyngitis
Pharyngitis
Pharyngitis is an inflammation of the throat or pharynx. In most cases it is quite painful, and is the most common cause of a sore throat.Like many types of inflammation, pharyngitis can be acute – characterized by a rapid onset and typically a relatively short course – or chronic....
, and/or nasal congestion.
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, rarely they may still occur. Additionally, there is also a small risk of cross-reactivity in patients who have experienced angioedema
Angioedema
Angioedema or Quincke's edema is the rapid swelling of the dermis, subcutaneous tissue, mucosa and submucosal tissues. It is very similar to urticaria, but urticaria, commonly known as hives, occurs in the upper dermis...
with ACE inhibitor therapy.
Myocardial infarction: the controversy
The issue of whether angiotensin II receptor antagonists slightly increase the risk of heart attack (myocardial infarction - MI) is currently being investigated. Some studies suggest ARBs can increase the risk of myocardial infarction. However, other studies have found that ARBs do not increase the risk of MI. To date, there is no consensus on whether ARBs have a tendency to increase the risk of myocardial infarction, and further investigations are underway.FDA’s meta-analysis (06/02/2011)of 31 randomized controlled trials comparing ARBs to other treatment found no evidence of an increased risk of incident (new) cancer, cancer-related death, breast cancer, lung cancer, or prostate cancer in patients receiving ARBs.
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 AT2 receptor stimulation may be less beneficial than previously proposed, and may even be harmful under certain circumstances through mediation of growth promotion, fibrosis
Fibrosis
Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This is as opposed to formation of fibrous tissue as a normal constituent of an organ or tissue...
, and hypertrophy
Hypertrophy
Hypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells. It should be distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number...
, as well as proatherogenic and proinflammatory effects.