At1 receptor antagonists

Drugs that bind to AT1 receptors with very high affinity to prevent the effect of angiotensin II, which is mediated by these receptors. The drugs losartan and valsartan are competitive antagonists, while candesartan and olmesartan, for example, behave like non-competitive antagonists. The selectivity of the AT1 receptor blockers of the Sartan family is very high. Their AT1 inhibition potency is about 10,000 times higher than that of AT2 receptors.

Most Sartans are applied in their active form. Olmesartan and candesartan, on the other hand, are prodrugs (they are given in the form of their esterified precursors, candesartan celelextil and olmetarsan medoxomil, respectively), which are only converted into their active form after oral uptake. Esterases in the intestinal mucosa release the active ingredient).

Angiotensin II receptor blockers (AT1 receptor antagonists) lead to an almost complete blockage of the angiotensin II effect at its receptor (AT1 receptor). In this way they inhibit the renin-angiotensin-aldosterone system (RAAS) more completely than ACE inhibitors. On the other hand, they do not block bradykinin degradation, which explains why they trigger the side effects induced by bradykinin accumulation (e.g. dry irritable cough; angioneurotic edema, urticaria) much less frequently (compared to ACE inhibitors only in 25% of cases).

In addition, AT1 receptor antagonists, but not the ACE inhibitors, lead to an activation of AT2 receptors, since angiontensin II is blocked but still formed. This is the reason why angiotensin II can now interact more with the AT2 receptor. This effect on AT2 receptors (which are upregulated in arterial hypertension) contributes to the antihypertensive effect of AT1 receptor antagonists. Furthermore, the occupation of the AT1 receptors, whose feedback (negative feedback) prevents renin secretion, has an additional blood pressure-lowering effect.

Angiotensin II is a hormone that leads via AT1 receptor activation to a contraction of the smooth vascular muscles, i.e. to vasoconstriction and thus to an increase in blood pressure. Blocking the AT1 receptor by suitable pharmaceuticals (Sartane) leads to dilation of the vessels. AT1 receptor blockers also inhibit the release of aldosterone.

There is broad agreement that AT1 receptor antagonists can be considered as substitutes for ACE inhibitors in cases of intolerance.

Indications: chronic heart failure, left ventricular dysfunction after acute myocardial infarction, arterial hypertension.

For adult hypertension, doctors may prescribe any available Sartane. For children or adolescents between 6 and 18 years of age, only candesartan, losartan, olmesartan and valsartan are approved for the treatment of hypertension. Patients with heart failure may only be given candesartan, losartan and valsartan according to the approval documents.

The duration of action of the individual Sartans is almost the same, so that once daily administration is sufficient for all representatives.

For very high doses of valsartan, there are hardly any alternatives. At doses equivalent to valsartan 320 mg, azilsartan, eprosartan, irbesartan, losartan, olmesartan and also telmisartan would exceed the maximum daily doses allowed. Candesartan is the only representative approved for the equivalent required dose of 32 mg.

Dry cough (rather less than with ACE inhibitors), impaired taste, urticaria, itching, angioneurotic edema (much less frequent than with ACE inhibitors). Tolerance deteriorates significantly with the combined use of ACE inhibitors and AT-2 blockers.

Noteworthy is the so-called olmesartan enteropathy. However, this refers to all At1-receptor blocks (ARB). Of 73 published cases, 59 cases were olmesartan-associated, another 14 case reports were published for telmisartan (4), valsartan (3), losartan (2), candesartan (1) and eprosartan (1) (Wenzel RR et al. 2019). Based on the available cohort studies, ARB-associated intestinal malabsorption occurs in 9.8 to 14 cases per 100,000 patients treated with ARB. Although the majority of case reports with olmesartan have been published, no clear difference within ARBs can be excluded in the cohort studies (Wenzel RR et al. 2019).

• Hypersensitivity to the respective active substance
• second and third trimesters of pregnancy
• severe impairment of liver function
• Simultaneous use with aliskiren-containing drugs in patients with diabetes mellitus or impaired kidney function

From the group of angiotensin-2 receptor blockers (AT-2 blockers), the following preparations are approved for the therapy of heart failure, in some cases also in combination with ACE inhibitors.

• Losartan (Lorzaar®)
• Valsartan (Diovan®, Provas®)
• Candesartan (Blopress®)
• Azilsartan (Edarbi®)
• Telmisartan (Micardis®, Kinzalmono®)
• Olmesartan

There is broad agreement that AT1 receptor antagonists can be considered as substitutes for ACE inhibitors in cases of intolerance. Indications: chronic heart failure, left ventricular dysfunction after acute myocardial infarction, arterial hypertension.

Pharmacodynamically, the representatives of Sartane hardly differ from each other. However, there are major differences in their pharmacokinetic properties. For example, the bioavailability ranges from 13% for eprosartan to 80% for irbesartan. Despite these differences, no clinically relevant differences have been observed so far.

In terms of drug elimination, telmisartan is the only representative of the drug that differs from the other Sartans, which are eliminated in approximately equal proportions via the kidney and liver. Telmisartan, on the other hand, is excreted almost exclusively via the liver, which may be of relevance in severe liver diseases.

1. Graefe KH et al (2016) Pharmka with effect on the vascular system. In: Graefe KH et al (Eds) Pharmacology and Toxicology. Georg Thieme Publisher Stuttgart S.174-177

2. Wenzel RR et al (2019) Association of sprue-like enteropathy and angiotensin receptor-1 antagonists. Vienna Klin Weekly Report 131:493-501.