Hot Contents: Angiotensin receptor inhibitor

Angiotensin II receptor antagonist

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.

Discovery and development

Structure

Losartan, irbesartan, olmesartan, candesartan and valsartan include the tetrazole group (a ring with four nitrogen and one carbon).
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. Blockade of AT₁ receptors directly causes vasodilation, reduces secretion of vasopressin, and 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. For these three key PD/ PK areas that indicate efficacy, it is important to see that one needs a combination of all three 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 clinically important measurement relates to the amount of blockade or inhibition of the blood pressure-raising effect of angiotensin II. Pressor inhibition is not a measure of blood pressure (BP) efficacy, though. 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)

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:

Biological half life

The third area needed to complete the overall efficacy picture of an ARB is its biological half life. The half lives from the US FDA PIs are as follows:

Drug comparison and pharmacokinetics

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.

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 effect.

In 2008, they were reported to have a remarkable negative association with Alzheimer's disease (AD). 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 (ARBs) were 35—40% less likely to develop AD than those using other antihypertensives.

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 hemoglobin levels, renal impairment, pharyngitis, 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 with ACE inhibitor therapy.

Myocardial infarction: the controversy

The question of whether or not angiotensin II receptor antagonists slightly increase the risk of heart attack (myocardial infarction - MI) is currently being investigated. Some studies have demonstrated 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.

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, and hypertrophy , as well as and proinflammatory effects.

Cancer risk factors

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."

Longevity promotion

Knockout of the Agtr1a gene that encodes AT₁ results in marked prolongation of the life span of mice by 26% compared to controls by reducing oxidative damage especially to mitochondria and overexpression of renal prosurvival genes and the ARBs seem to have the same effect.

Fibrosis regression

Losartan and other ARBs regress liver, heart, lung and kidney fibrosis.

References

External links

MeSH Angiotensin+II+Type+1+Receptor+Blockers

Enzyme: Inducer • Inhibitor
Ion channel: Opener • Blocker
Receptor: Agonist • Antagonist • Positive allosteric modulator (PAM) • Negative allosteric modulator (NAM) • Inverse agonist
Transporter [Reuptake]: Enhancer (RE) • Inhibitor (RI) • Releaser (RA)
Miscellaneous: Precursor • Cofactor

Classes

Enzyme

see Enzyme inhibition

Ion channel

Calcium channel blocker (CCB) • Potassium channel blocker (PCB) • Sodium channel blocker (SCB) • Potassium channel opener (PCO)

Receptor &
transporter

BA/ M

Adrenergic	Adrenergic receptor agonist ( α, β ( 1, 2)) • Adrenergic receptor antagonist ( α ( 1, 2), β) • Adrenergic reuptake inhibitor (ARI)

Dopaminergic	Dopamine receptor agonist • Dopamine receptor antagonist • Dopamine reuptake inhibitor (DRI)

Histaminergic	Histamine receptor agonist • Histamine receptor antagonist ( H₁, H₂, H₃)

Serotonergic	Serotonin receptor agonist • Serotonin Receptor Antagonist ( 5-HT₃) • Serotonin reuptake inhibitor (SRI) • Serotonin reuptake enhancer (SRE)


GABAergic	GABA receptor agonist • GABA receptor antagonist • GABA reuptake inhibitor (GRI)

Glutamatergic	Glutamate receptor agonist ( AMPA) • Glutamate receptor antagonist ( NMDA)